Method of producing highly functionalized 1,3-diamino-propan-2-ols from solid support

ABSTRACT

The invention is directed to compounds and methods of synthesizing hydroxyethlamino amides and their use in treatment of aspartyl protease mediated diseases and conditions.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application60/527963 filed Dec. 9, 2003 and hereby fully incorporated by reference.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

The research and development of the invention described below was notfederally sponsored.

BACKGROUND OF THE INVENTION

The present invention is directed to synthetic routes to prepareaspartic protease inhibitors and in particular, hydroxyethyl amineinhibitors. The present invention is also directed to syntheticintermediates along those routes, and to the inhibitors, themselves. Theuse of parallel synthetic sequences to prepare focused chemicallibraries directed toward a specific protein family, when leveraged by asuitably broad synthetic method, is a highly valuable approach for hitgeneration in drug discovery because a hit to any member of that proteinfamily may be identified and the speed in which analogs may be preparedin a subsequent hit to lead program is substantially increased.

The aspartyl protease family includes: HIV protease, cathepsins,β-secretase, renin, and plasmepsin. A number of native andenzyme-inhibitor crystal structures have been solved for the aboveaspartic proteases. A key structural element in most inhibitors is ahydroxyl or hydroxyl like moiety that binds to the catalytically activeaspartic acids in the enzyme active site. Work toward the development ofmechanism pathway inhibitors for this family of enzymes has resulted inthe identification of a number of transition-state analogue units, whichare effective for inhibiting aspartic proteases.

Two of the most useful of these transition-state analogue units are thehydroxyethylene and hydroxyethylamine units; the later isostere has beenemployed extensively in agents for the treatment of AIDS and arecurrently used in clinical practice (Lebon, F.; Ledecq, M. Curr. Med.Chem. 2000, 7, 455-477).

Other solid-phase and/or parallel approaches to synthesis ofhydroxyethyl amines have been described. Tamamura, H. et al., Org.Biomol. Chem. 2003, 1, 2468-2473 describe a solid phase synthesis ofhydroxyethylamine dipeptide isosteres but do not describe or suggest themethods or compounds of the present invention. U.S. Pat. No. 6,150,416to Kick et al. describes hydroxyethylamine compounds that bind cathepsinD, but does not describe or suggest the methods or compounds of thepresent invention. Kick, E. K.; Ellman, J. A. J. Med. Chem. 1995, 38,1427-1430 describe the solid phase synthesis of hydroxyethylaminoaspartyl protease inhibitors, but does not describe or suggest themethods or compounds of the present invention. Baker, C. T. et al.,Bioorg. Med. Chem. Lett. 1998, 8, 3631-3636 also describe the solidphase synthesis of hydroxyethylamino aspartyl protease inhibitors, butdoes not describe or suggest the methods or compounds of the presentinvention. Chino, M. et al., Tetrahedron 2002, 58, 6305-6310 alsodescribe the solid phase synthesis of hydroxyethylamino aspartylprotease inhibitors, but does not describe or suggest the methods orcompounds of the present invention. None of these prior approachesprovides as flexible or efficient a means of synthesizing hydroxyethylamines as does the present invention

Dörner, B. et al. (Bioorg. Med. Chem. 1996, 4, 709-715) describe asolid-phase synthetic method for generating alkylated amides using ninesuccessive cycles exposing a support-bound amide to lithiumtert-butoxide followed by quenching with electrophile. Such a method,however, cannot provide the epoxyalkyl intermediates useful in thepresent invention in practical yields.

Thus, a solid phase method has been developed to generatehydroxyethylamino amides, a known aspartyl protease isostere. We havepreformed the eight step sequence and obtained the resultinghydroxyethylamino amides in good yield without the need for rigorousexclusion of water or oxygen. The procedure draws on large reagentpools: carboxylic acids, 1° amines, and aldehydes; which results in avirtual library of over 1 trillion compounds. In addition, we havedeveloped a general method for the monoalkylation of Rink type resins.

SUMMARY OF THE INVENTION

The present invention is directed to methods of synthesizing ahydroxyethlamino amide of Formula (I):

wherein:

R¹ is C₁₋₈alkanyl, cyclicC₁₋₈alkanyl, C₆₋₁₄aryl, C₅₋₁₄heteroarylC₂₋₈alkenyl, C₁₋₈alkoxy(C₂₋₈)alkenyl, C₂₋₈alkynyl,C₁₋₈alkoxy(C₂₋₈)alkynyl, heteroaryl(C₂₋₈)alkenyl, orheteroaryl(C₂₋₈)alkynyl; wherein said C₁₋₈alkanyl, cyclicC₁₋₈alkanyl,C₆₋₁₄aryl, C₅₋₁₄heteroaryl C₂₋₈alkenyl, C₁₋₈alkoxy(C₂₋₈)alkenyl,C₂₋₈alkynyl, C₁₋₈alkoxy(C₂₋₈)alkynyl, heteroaryl(C₂₋₈)alkenyl, andheteroaryl(C₂₋₈)alkynyl are optionally substituted with one to twosubstituents independently selected from the group consisting ofC₆₋₁₄aryloxy, diC₁₋₈alkanylamino, C₁₋₈alkanylamino, C₁₋₈alkanyl,C₆₋₁₄aryl, C₁₋₈alkanyloxy, C₁₋₈alkanylcarbonyl, perhaloC₁₋₆alkanyl,halo, C₅₋₁₄heteroaryl, C₁₋₈alkanyl, C₁₋₈alkanylthio,oxoC₅₋₈cyclicheteroalkenyl, C₆₋₁₄arylalkynyl, C₁₋₈alkanylsulfonyl,C₆₋₁₄arylC₁₋₈alkanyl, C₁₋₈alkanyloxy, C₆₋₁₄arylC₁₋₈alkanyloxy,C₆₋₁₄arylC₁₋₈alkanyloxycarbonylamino, and C₁₋₈alkanylcarbonylamino;

R² is C₁₋₈alkanyl, C₂₋₈alkenyl, C₁₋₈alkoxy(C₂₋₈)alkenyl, C₂₋₈alkynyl,C₁₋₈alkanyloxy(C₂₋₈)alkynyl, heteroaryl(C₂₋₈)alkenyl,heteroaryl(C₂₋₈)alkynyl hydrogen, or N-linked-C₁₋₈alkanylcarbonylamino,wherein the C₁₋₈alkanyl, C₁₋₈alkenyl C₂₋₈alkynyl portions of R² areoptionally substituted with one or two substituents independentlyselected from the group consisting of C₁₋₈alkanylC₆₋₁₄aryl,C₁₋₈alkanyloxyC₆₋₁₄aryl, C₅₋₁₄heteroaryl, C₆₋₁₄aryl, or C₆₋₁₄aryl;

R³ is C₁₋₈alkanyl, C₂₋₈alkenyl, C₁₋₈alkoxy(C₂₋₈)alkenyl, C₂₋₈alkynyl,C₁₋₈alkoxy(C₂₋₈)alkynyl, heteroaryl(C₂₋₈)alkenyl,heteroaryl(C₂₋₈)alkynyl, C₁₋₈alkanyl, cyclicC₁₋₈alkanyl, C₆₋₁₄aryl, orC₅₋₁₄heteroaryl; wherein said C₁₋₈alkanyl, cyclicC₁₋₈alkanyl, C₆₋₁₄aryl,and C₅₋₁₄heteroaryl is optionally and independently substituted with oneor two substituent selected from the group consisting of(C₁₋₈alkanylthio)(aminocarbonyl), C₁₋₈alkanylaminocarbonyl,(C₈₋₁₄aryl)(C₁₋₈alkanylaminocarbonyl), amino, aminosulfonylC₆₋₁₄aryl,C₁₋₈alkanylC₃₋₈cyclicheteroalkanyl, C₁₋₈alkanyloxycarbonylamino,C₁₋₈alkanylC₆₋₁₄arylamino, C₁₋₈alkanylC₆₋₁₄aryl,C₁₋₈alkanyloxyC₆₋₁₄aryl, C₃₋₈cyclicheteroalkanyl, C₆₋₁₄aryl,C₆₋₁₄arylC₁₋₈alkanyloxycarbonylamino, C₆₋₁₄aryloxy,C₆₋₁₄aryloxyC₆₋₁₄aryl, diC₁₋₈alkanyloxyC₆₋₁₄aryl, dihaloC₆₋₁₄arylhaloC₆₋₁₄aryl, and oxoC₃₋₈cyclicheteroalkanyl; C₆₋₁₄aryl wherein saidaryl is optionally and independently substituted with a substituentselected from the group consisting of C₁₋₈alkanyl, and C₆₋₁₄aryloxy;C₁₋₈alkanykC₃₋₈cyclicheteroalkanyl; C₅₋₁₄heteroaryl;C₆₋₁₄arylC₁₋₈alkanylheteroalkanyl; or C₃₋₈cyclicheteroalkanyl; and andenantiomers, diastereomers, tautomers, solvates, or pharmaceuticallyacceptable salts thereof, the method comprising:

(a) preparing a epoxymethylated support of formula (Ia)

wherein (support) is selected from the group consisting of amine basedpolystyrene resins;

(b) reacting the support of formula (Ia) with an R¹ carboxylic acid orderivative of the formula R¹COY wherein Y is OH, Cl, Br, OC₁₋₃alkanyl orOOCR¹ to generate an epoxymethylated amido support of formula (Ib)

(c) reacting the epoxymethylated amido support of formula (Ib) with anR² amine of the formula R²NH₂ to generate a hydroxyethlamino amidosupport of formula (Ic)

(d) reacting the hydroxyethlamino amido support of formula (Ic) with anR³ aldehyde of the formula R³CHO to generate a hydroxyethlamino amidosupport of formula (Id)

and

(e) cleaving the hydroxyethlamino amide of formula (I) from thehydroxyethlamino amido support of formula (Id).

The present invention is also directed to pharmaceutical compositionscontaining compounds of Formula (I).

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the following underlined terms are intended to have thefollowing meanings:

“C_(a-b)” (where a and b are integers) refers to a radical containingfrom a to b carbon atoms inclusive, or in the case of a radical withheteroatoms, refers to a radical containing from a to b atoms includingboth carbon and heteroatoms. For example, C₁₋₃alkanyl denotes a analkanyl radical containing 1, 2 or 3 carbon atoms, and C₄₋₇heteroalkanyldenotes a heteroalkanyl containing from 4 to 7 atoms including bothcarbon atoms and heteroatoms.

“Alkyl:” refers to a saturated or unsaturated, branched, straight-chainor cyclic monovalent hydrocarbon radical derived by the removal of onehydrogen atom from a single carbon atom of a parent alkane, alkene oralkyne. Typical alkyl groups include, but are not limited to, methyl;ethyls such as ethanyl, ethenyl, ethynyl; propyls such as propan-1-yl,propan-2-yl, cyclopropan-1-yl ( ), prop-1-en-1-yl, prop-1-en-2-yl,prop-2-en-1-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl,prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butyls such as butan-1-yl,butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl,but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl,but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl,cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl,but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like. Wherespecific levels of saturation are intended, the nomenclature “alkanyl”,“alkenyl” and/or “alkynyl” is used, as defined below. In preferredembodiments, the alkyl groups are (C₁-C₆) alkyl, with (C₁-C₃) beingparticularly preferred.

“Alkanyl:” refers to a saturated branched, straight-chain or cyclicmonovalent hydrocarbon radical derived by the removal of one hydrogenatom from a single carbon atom of a parent alkane. Typical alkanylgroups include, but are not limited to, methanyl; ethanyl; propanylssuch as propan-1-yl, propan-2-yl, cyclopropan-1-yl, etc.; butyanyls suchas butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl,cyclobutan-1-yl, etc.; and the like. In preferred embodiments, thealkanyl groups are (C₁₋₈) alkanyl, with (C₁₋₃) being particularlypreferred.

“Alkenyl” refers to an unsaturated branched, straight-chain or cyclicmonovalent hydrocarbon radical having at least one carbon-carbon doublebond derived by the removal of one hydrogen atom from a single carbonatom of a parent alkene. The radical may be in either the cis or transconformation about the double bond(s). Typical alkenyl groups include,but are not limited to, ethenyl; propenyls such as prop-1-en-1-yl,prop-1-en-2-yl, prop-2-en-1-yl, prop-2-en-2-yl, cycloprop-1-en-1-yl;cycloprop-2-en-1-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl,2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl,buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl,cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, etc.; and the like.

“Alkenyl” refers to an unsaturated branched, straight-chain or cyclicmonovalent hydrocarbon radical having at least one carbon-carbon triplebond derived by the removal of one hydrogen atom from a single carbonatom of a parent alkyne. Typical alkynyl groups include, but are notlimited to, ethynyl; propynyls such as prop-1-yn-1-yl, prop-2-yn-1-yl,etc.; butynyls such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl,etc.; and the like.

“Heteroalkyl” and Heteroalkanyl” refer to alkyl or alkanyl radicals,respectively, in which one or more carbon atoms (and any necessaryassociated hydrogen atoms) are independently replaced with the same ordifferent heteroatoms (including any necessary hydrogen or other atoms).Typical heteroatoms to replace the carbon atom(s) include, but are notlimited to, N, P, O, S, Si, etc. Preferred heteroatoms are O, N and S.Thus, heteroalkanyl radicals can contain one or more of the same ordifferent heteroatomic groups, including, by way of example and notlimitation, epoxy (—O—), epidioxy (—O—O—), thioether (—S—), epidithio(—SS—), epoxythio (—O—S—), epoxyimino (—O—NR′—), imino (—NR′—), biimmino(—NR′—NR′—), azino (═N—N═), azo (—N═N—), azoxy (—N—O—N—), azimino(—NR′—N═N—), phosphano (—PH—), λ⁴-sulfano (—SH₂—), sulfonyl (—S(O)₂—),and the like, where each R′ is independently hydrogen or (C₁-C₆) alkyl.

“Parent Aromatic Ring System:” refers to an unsaturated cyclic orpolycyclic ring system having a conjugated λ electron system.Specifically included within the definition of “parent aromatic ringsystem” are fused ring systems in which one or more rings are aromaticand one or more rings are saturated or unsaturated, such as, forexample, indane, indene, phenalene, etc. Typical parent aromatic ringsystems include, but are not limited to, aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene,fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene,s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene,ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene,phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene,rubicene, triphenylene, trinaphthalene, and the like

“Aryl:” refers to a monovalent aromatic hydrocarbon radical derived bythe removal of one hydrogen atom from a single carbon atom of a parentaromatic ring system. Typical aryl groups include, but are not limitedto, radicals derived from aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene,fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene,s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene,ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene,phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene,rubicene, triphenylene, trinaphthalene, and the like. In preferredembodiments, the aryl group is (C₅₋₂₀) aryl, with (C₅₋₁₀) beingparticularly preferred. Particularly preferred aryl groups are phenyland naphthyl groups.

“Arylalkyl:” refers to an acyclic alkyl group in which one of thehydrogen atoms bonded to a carbon atom, typically a terminal carbonatom, is replaced with an aryl radical. Typical arylalkyl groupsinclude, but are not limited to, benzyl, 2-phenylethan-1-yl,2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl,2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and thelike. Where specific alkyl moieties are intended, the nomenclaturearylalkanyl, arylakenyl and/or arylalkynyl is used. [In preferredembodiments, the arylalkyl group is (C₆₋₂₆) arylalkyl, e.g., thealkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C₁₋₆) andthe aryl moiety is (C₅₋₂₀). In particularly preferred embodiments thearylalkyl group is (C₆₋₁₃), e.g., the alkanyl, alkenyl or alkynyl moietyof the arylalkyl group is (C₁₋₃) and the aryl moiety is (C₅₋₁₀). Evenmore preferred arylalkyl groups arephenylalkanyls.

“Alkanyloxy:” refers to a saturated branched, straight-chain or cyclicmonovalent hydrocarbon alcohol radical derived by the removal of thehydrogen atom from the hydroxide oxygen of the alcohol. Typicalalkanyloxy groups include, but are not limited to, methanyl; ethanyloxy;propanyloxy groups such as propan-1-yloxy (CH₃CH₂CH₂O—), propan-2-yloxy((CH₃)₂CHO—), cyclopropan-1-yloxy, etc.; butyanyloxy groups such asbutan-1-yloxy, butan-2-yloxy, 2-methyl-propan-1-yloxy,2-methyl-propan-2-yloxy, cyclobutan-1-yloxy, etc.; and the like. Inpreferred embodiments, the alkanyloxy groups are (C₁₋₈) alkanyloxygroups, with (C₁₋₃) being particularly preferred.

“Parent Heteroaromatic Ring System:” refers to a parent aromatic ringsystem in which one carbon atom is replaced with a heteroatom.Heteratoms to replace the carbon atoms include N, O, and S. Specificallyincluded within the definition of “parent heteroaromatic ring systems”are fused ring systems in which one or more rings are aromatic and oneor more rings are saturated or unsaturated, such as, for example,arsindole, chromane, chromene, indole, indoline, xanthene, etc. Typicalparent heteroaromatic ring systems include, but are not limited to,carbazole, imidazole, indazole, indole, indoline, indolizine, isoindole,isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine,oxadiazole, oxazole, purine, pyran, pyrazine, pyrazole, pyridazine,pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline,quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene,triazole, xanthene, and the like.

“Heteroaryl:” refers to a monovalent heteroaromatic radical derived bythe removal of one hydrogen atom from a single atom of a parentheteroaromatic ring system. Typical heteroaryl groups include, but arenot limited to, radicals derived from carbazole, imidazole, indazole,indole, indoline, indolizine, isoindole, isoindoline, isoquinoline,isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, purine,pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole,pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline,tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and thelike. In preferred embodiments, the heteroaryl group is a 5-20 memberedheteroaryl, with 5-10 membered heteroaryl being particularly preferred.

“Cyclicheteroalkyl:” refers to a saturated or unsaturated monocyclic orbicyclic alkyl radical in which one carbon atom is replaced with N, O orS. In certain specified embodiments the cycloheteroalkyl may contain upto four heteroatoms independently selected from N, O or S. Typicalcycloheteroalkyl moieties include, but are not limited to, radicalsderived from imidazolidine, morpholine, piperazine, piperidine,pyrazolidine, pyrrolidine, quinuclidine, and the like. In preferredembodiments, the cycloheteroalkyl is a 3-6 membered cycloheteroalkyl.

“Cyclicheteroalkanyl:” refers to a saturated monocyclic or bicyclicalkanyl radical in which one carbon atom is replaced with N, O or S. Incertain specified embodiments the cycloheteroalkanyl may contain up tofour heteroatoms independently selected from N, O or S. Typicalcycloheteroalkanyl moieties include, but are not limited to, radicalsderived from imidazolidine, morpholine, piperazine, piperidine,pyrazolidine, pyrrolidine, quinuclidine, and the like. In preferredembodiments, the cycloheteroalkanyl is a 3-6 memberedcycloheteroalkanyl.

“Cyclicheteroalkenyl:” refers to a saturated monocyclic or bicyclicalkenyl radical in which one carbon atom is replaced with N, O or S. Incertain specified embodiments the cycloheteroalkenyl may contain up tofour heteroatoms independently selected from N, O or S. Typicalcycloheteroalkenyl moieties include, but are not limited to, radicalsderived from imidazoline, pyrazoline, pyrroline, indoline, pyran, andthe like. In preferred embodiments, the cycloheteroalkanyl is a 3-6membered cycloheteroalkanyl.

“Substituted:” refers to a radical in which one or more hydrogen atomsare each independently replaced with the same or differentsubstituent(s). Typical substituents include, but are not limited to,—X, —R, —O⁻, ═O, —OR, —O—OR, —SR, —S⁻, ═S, —NRR, ═NR, —CX₃, —CN, —OCN,—SCN, —NCO, —NCS, —NO, —NO₂, ═N₂, —N₃, —NHOH, —S(O)₂O⁻, —S(O)₂OH,—S(O)₂R, —P(O)(O⁻)₂, —P(O)(OH)₂, —C(O)R, —C(O)X, —C(S)R, —C(S)X,—C(O)OR, —C(O)O⁻, —C(S)OR, —C(O)SR, —C(S)SR, —C(O)NRR, —C(S)NRR and—C(NR)NRR, where each X is independently a halogen (preferably —F, —Clor —Br) and each R is independently —H, alkyl, alkanyl, alkenyl,alkynyl, alkylidene, alkylidyne, aryl, arylalkyl, arylheteroalkyl,heteroaryl, heteroarylalkyl or heteroaryl-heteroalkyl, as definedherein. Preferred substituents include hydroxy, halogen, C₁₋₈alkyl,C₁₋₈alkanyloxy, fluorinated alkanyloxy, fluorinated alkyl,C₁₋₈alkylthio, C₃₋₈cycloalkyl, C₃₋₈cycloalkanyloxy, nitro, amino,C₁₋₈alkylamino, C₁₋₈dialkylamino, C₃₋₈cycloalkylamino, cyano, carboxy,C₁₋₇alkanyloxycarbonyl, C₁₋₇alkylcarbonyloxy, formyl, carbamoyl, phenyl,aroyl, carbamoyl, amidino, (C₁₋₈alkylamino)carbonyl, (arylamino)carbonyland aryl(C₁₋₈alkyl)carbonyl.

“Support” refers to a solid support suitable for use in solid-phaseorganic synthesis. Preferred supports are those suitable for use in anautomated synthesis apparatus. Suitable supports include amine basedpolystyrene resins. Most preferred are Rink-type resins, andparticularly, Rink-AM resin beads.

With reference to substituents, the term “independently” means that whenmore than one of such substituent is possible, such substituents may bethe same or different from each other.

Throughout this disclosure, the terminal portion of the designated sidechain is described first, followed by the adjacent functionality towardthe point of attachment. Thus, for example, a“phenylC₁₋₆alkanylaminocarbonylC₁₋₆alkyl” substituent refers to a groupof the formula

The present invention is directed to methods of synthesizing ahydroxyethlamino amide of Formula (I):

wherein:

R¹ is C₁₋₈alkanyl, cyclicC₁₋₈alkanyl, C₆₋₁₄aryl, C₅₋₁₄heteroarylC₂₋₈alkenyl, C₁₋₈alkoxy(C₂₋₈)alkenyl, C₂₋₈alkynyl,C₁₋₈alkoxy(C₂₋₈)alkynyl, heteroaryl(C₂₋₈)alkenyl, orheteroaryl(C₂₋₈)alkynyl; wherein said C₁₋₈alkanyl, cyclicC₁₋₈alkanyl,C₆₋₁₄aryl, C₅₋₁₄heteroaryl C₂₋₈alkenyl, C₁₋₈alkoxy(C₂₋₈)alkenyl,C₂₋₈alkynyl, C₁₋₈alkoxy(C₂₋₈)alkynyl, heteroaryl(C₂₋₈)alkenyl, andheteroaryl(C₂₋₈)alkynyl are optionally substituted with one to twosubstituents independently selected from the group consisting ofC₆₋₁₄aryloxy, diC₁₋₈alkanylamino, C₁₋₈alkanylamino, C₁₋₆alkanyl,C₆₋₁₄aryl, C₁₋₈alkanyloxy, C₁₋₈alkanylcarbonyl, perhaloC₁₋₆alkanyl,halo, C₅₋₁₄heteroaryl, C₁₋₈alkanyl, C₁₋₈alkanylthio,oxoC₅₋₈cyclicheteroalkenyl, C₆₋₁₄arylalkynyl, C₁₋₈alkanylsulfonyl,C₆₋₁₄arylC₁₋₈alkanyl, C₁₋₈alkanyloxy, C₆₋₁₄arylC₁₋₈alkanyloxy,C₆₋₁₄arylC₁₋₈alkanyloxycarbonylamino, and C₁₋₈alkanylcarbonylamino;

R² is C₁₋₈alkanyl, C₂₋₈alkenyl, C₁₋₈alkoxy(C₂₋₈)alkenyl, C₂₋₈alkynyl,C₁₋₈alkanyloxy(C₂₋₈)alkynyl, heteroaryl(C₂₋₈)alkenyl,heteroaryl(C₂₋₈)alkynyl hydrogen, or N-linked-C₁₋₈alkanylcarbonylamino,wherein the C₁₋₈alkanyl, C₁₋₈alkenyl C₂₋₈alkynyl portions of R² areoptionally substituted with one or two substituents independentlyselected from the group consisting of C₁₋₈alkanylC₆₋₁₄aryl,C₁₋₈alkanyloxyC₆₋₁₄aryl, C₅₋₁₄heteroaryl, C₆₋₁₄aryl, or C₆₋₁₄aryl;

R³ is C₁₋₈alkanyl, C₂₋₈alkenyl, C₁₋₈alkoxy(C₂₋₈)alkenyl, C₂₋₈alkynyl,C₁₋₈alkoxy(C₂₋₈)alkynyl, heteroaryl(C₂₋₈)alkenyl,heteroaryl(C₂₋₈)alkynyl, C₁₋₈alkanyl, cyclicC₁₋₈alkanyl, C₆₋₁₄aryl, orC₅₋₁₄heteroaryl; wherein said C₁₋₈alkanyl, cyclicC₁₋₈alkanyl, C₆₋₁₄aryl,and C₅₋₁₄heteroaryl is optionally and independently substituted with oneor two substituent selected from the group consisting of(C₁₋₈alkanylthio)(aminocarbonyl), C₁₋₈alkanylaminocarbonyl,(C₆₋₁₄aryl)(C₁₋₈alkanylaminocarbonyl), amino, aminosulfonylC₆₋₁₄aryl,C₁₋₈alkanylC₃₋₈cyclicheteroalkanyl, C₁₋₈alkanyloxycarbonylamino,C₁₋₈alkanylC₆₋₁₄arylamino, C₁₋₈alkanylC₆₋₁₄aryl,C₁₋₈alkanyloxyC₆₋₁₄aryl, C₃₋₈cyclicheteroalkanyl, C₆₋₁₄aryl,C₆₋₁₄arylC₁₋₈alkanyloxycarbonylamino, C₆₋₁₄aryloxy,C₆₋₁₄aryloxyC₆₋₁₄aryl, diC₁₋₈alkanyloxyC₆₋₁₄aryl, dihaloC₆₋₁₄arylhaloC₆₋₁₄aryl, and oxoC₃₋₈cyclicheteroalkanyl; C₆₋₁₄aryl wherein saidaryl is optionally and independently substituted with a substituentselected from the group consisting of C₁₋₈alkanyl, and C₆₋₁₄aryloxy;C₁₋₈alkanylC₃₋₈cyclicheteroalkanyl; C₅₋₁₄heteroaryl;C₆₋₁₄arylC₁₋₈alkanylheteroalkanyl; or C₃₋₈cyclicheteroalkanyl; and andenantiomers, diastereomers, tautomers, solvates, or pharmaceuticallyacceptable salts thereof, the method comprising:

(a) preparing a epoxymethylated support of formula (Ia)

(Ia)

wherein (support) is selected from the group consisting of amine basedpolystyrene resins;

(b) reacting the support of formula (Ia) with an R¹ carboxylic acid orderivative of the formula R¹COY wherein Y is OH, Cl, Br, OC₁₋₃alkanyl orOOCR¹ to generate an epoxymethylated amido support of formula (Ib)

(c) reacting the epoxymethylated amido support of formula (Ib) with anR² amine of the formula R²NH₂ to generate a hydroxyethlamino amidosupport of formula (Ic)

(d) reacting the hydroxyethlamino amido support of formula (Ic) with anR³ aldehyde of the formula R³CHO to generate a hydroxyethlamino amidosupport of formula (Id)

and

(e) cleaving the hydroxyethlamino amide of formula (I) from thehydroxyethlamino amido support of formula (Id).

The present invention is also directed to methods of synthesizing ahydroxyethlamino amide of Formula (I):

wherein:

R¹ is C₁₋₈alkanyl, cyclicC₁₋₈alkanyl, C₆₋₁₄aryl, or C₅₋₁₄heteroaryl;wherein said C₁₋₈alkanyl, cyclicC₁₋₈alkanyl, C₆₋₁₄aryl, andC₅₋₁₄heteroaryl are optionally substituted with one to two substituentsindependently selected from the group consisting of C₆₋₁₄aryloxy,diC₁₋₈alkanylamino, C₁₋₈alkanylamino, C₁₋₈alkanyl, C₆₋₁₄aryl,C₁₋₈alkanyloxy, C₁₋₈alkanylcarbonyl, perhaloC₁₋₆alkanyl, halo,C₅₋₁₄heteroaryl, C₁₋₈alkanyl, C₁₋₈alkanylthio,oxoC₅₋₈cyclicheteroalkenyl, C₆₋₁₄arylalkynyl, C₁₋₈alkanylsulfonyl,C₆₋₁₄arylC₁₋₈alkanyl, C₁₋₈alkanyloxy, C₆₋₁₄arylC₁₋₈alkanyloxy,C₆₋₁₄arylC₁₋₈alkanyloxycarbonylamino, and C₁₋₈alkanylcarbonylamino;

R² is C₁₋₈alkanyl, C₁₋₈alkenyl, hydrogen, orN-linked-C₁₋₈alkanylcarbonylamino, wherein said C₁₋₈alkanyl andC₁₋₈alkenyl are optionally substituted with one or two substituentsindependently selected from the group consisting ofC₁₋₈alkanylC₆₋₁₄aryl, C₁₋₈alkanyloxyC₆₋₁₄aryl, C₅₋₁₄heteroaryl,C₆₋₁₄aryl, or C₆₋₁₄aryl;

R³ is C₁₋₈alkanyl wherein said C₁₋₈alkanyl is optionally andindependently substituted with one or two substituent selected from thegroup consisting of (C₁₋₈alkanylthio)(aminocarbonyl),C₁₋₈alkanylaminocarbonyl, (C₆₋₁₄aryl)(C₁₋₈alkanylaminocarbonyl), amino,aminosulfonylC₆₋₁₄aryl, C₁₋₈alkanylC₃₋₈cyclicheteroalkanyl,C₁₋₈alkanyloxycarbonylamino, C₁₋₈alkanylC₆₋₁₄arylamino,C₁₋₈alkanylC₆₋₁₄aryl, C₁₋₈alkanyloxyC₆₋₁₄aryl, C₃₋₈cyclicheteroalkanyl,C₆₋₁₄aryl, C₆₋₁₄arylC₁₋₈alkanyloxycarbonylamino, C₆₋₁₄aryloxy,C₆₋₁₄aryloxyC₆₋₁₄aryl, diC₁₋₈alkanyloxyC₆₋₁₄aryl, dihaloC₆₋₁₄arylhaloC₆₋₁₄aryl, and oxoC₃₋₈cyclicheteroalkanyl ; C₆₋₁₄aryl wherein saidaryl is optionally and independently substituted with a substituentselected from the group consisting of C₁₋₈alkanyl, and C₆₋₁₄aryloxy;C₁₋₈alkanylC₃₋₈cyclicheteroalkanyl; C₅₋₁₄heteroaryl;C₆₋₁₄arylC₁₋₈alkanylheteroalkanyl; or C₃₋₈cyclicheteroalkanyl; and andenantiomers, diastereomers, tautomers, solvates, or pharmaceuticallyacceptable salts thereof, the method comprising:

(a) preparing a epoxymethylated support of formula (Ia)

wherein (support) is selected from the group consisting of amine basedpolystyrene resins;

(b) reacting the support of formula (Ia) with an R¹ carboxylic acid orderivative of the formula R¹COY wherein Y is OH, Cl, Br, OC₁₋₃alkanyl orOOCR¹ to generate an epoxymethylated amido support of formula (Ib)

(c) reacting the epoxymethylated amido support of formula (Ib) with anR² amine of the formula R²NH₂ to generate a hydroxyethlamino amidosupport of formula (Ic)

(d) reacting the hydroxyethlamino amido support of formula (Ic) with anR³ aldehyde of the formula R³CHO to generate a hydroxyethlamino amidosupport of formula (Id)

and

(e) cleaving the hydroxyethlamino amide of formula (I) from thehydroxyethlamino amido support of formula (Id).

Embodiments of the present invention include those wherein:

(a) Y is OH;

(b) (support) is selected from the group consisting of amine basedpolystyrene resins;

(c) (support) is a Rink-type resin;

(d) (support) is Rink-AM resin;

(e) the alkanyl in substituted C₁₋₈alkanyl and C₁₋₈alkanyl-substitutedsubstituents is methyl or ethyl;

(f) the aryl in substituted and unsubstituted C₆₋₁₄aryl substituents isphenyl or naphthyl;

(g) the aryl in substituted and unsubstituted C₆₋₁₄aryl substituents isphenyl;

(h) halo is F or Cl;

R¹ is optionally substituted phenyl or optionally substituted naphthyl;

(j) R¹ is optionally substituted phenyl;

(k) R¹ is optionally substituted pyridyl and pyrazinyl, quinolyl, orfuryl;

(l) R¹ is C₆₋₁₄aryloxyC₆₋₁₄aryl;

(m) R¹ is diC₁₋₈alkanylaminoC₆₋₁₄aryl;

(n) R¹ is C₁₋₈alkanylC₆₋₁₄aryl, C₆₋₁₄arylC₁₋₈alkanyl, ordiC₁₋₈alkanyloxyC₆₋₁₄aryl;

(o) R¹ is C₁₋₈alkanylcarbonylC₆₋₁₄aryl;

(p) R¹ is perhaloC₁₋₆alkanylC₆₋₁₄aryl;

(q) R¹ is haloC₅₋₁₄heteroaryl, or C₅₋₁₄heteroaryl;

(r) R¹ is C₅₋₁₄heteroaryl, C₁₋₈alkanylC₅₋₁₄heteroaryl,cyclicC₁₋₈alkanyl, or C₁₋₈alkanylthioC₁₋₈alkanyl;

(s) R¹ is oxoC₅₋₈cyclicheteroalkenyl;

(t) R¹ is C₁₋₈alkanyl, or C₆₋₁₄arylalkynyl;

(u) R¹ is C₁₋₈alkanylsulfonylC₁₋₈alkanyl;

(v) R¹ is C₆₋₁₄arylC₁₋₈alkanylC₆₋₁₄aryl, C₁₋₈alkanyloxyC₆₋₁₄aryl,C₁₋₈alkanylC₆₋₁₄aryl, C₆₋₁₄arylC₁₋₈alkanyloxyC₆₋₁₄aryl,C₆₋₁₄arylC₁₋₈alkanyloxycarbonylaminoC₁₋₈alkanyl, orC₁₋₈alkanylcarbonylaminoC₁₋₈alkanyl;;

(w) R² is C₆₋₁₄arylC₁₋₈alkanyl, diC₆₋₁₄arylC₁₋₈alkanyl, C₁₋₈alkanyl,alkenyl, hydrogen, or N-linked-C₁₋₈alkanylcarbonylamino;

(x) R² is C₁₋₈alkanyl;

(y) R² is C₆₋₁₄arylC₁₋₈alkanyl;

(z) R² is C₁₋₈alkanyl, or C₆₋₁₄arylC₁₋₈alkanyl;

(aa) R² is hydrogen, C₁₋₈alkanyloxyC₆₋₁₄arylC₁₋₈alkanyl;

(bb) R² is hydrogen, C₁₋₈alkanyloxyC₆₋₁₄arylC₁₋₈alkanyl, orC₁₋₈alkanylC₆₋₁₄arylC₁₋₈alkanyl;

(cc) R² is hydrogen;

(dd) R² is hydrogen, C₁₋₈alkanyl, C₅₋₁₄heteroarylC₁₋₈alkanyl,C₆₋₁₄arylC₁₋₈alkanyl;

(ee) R³ is optionally substituted pyridinyl, thienyl, THF, morpholine,or piperidine;

(ff) R³ is optionally substituted C₁₋₈alkanyl;

(gg) R³ is C₁₋₈alkanyloxyC₆₋₁₄arylC₁₋₈alkanyl;

(hh) R³ is C₁₋₈alkanyloxyC₆₋₁₄arylC₁₋₈alkanyl,dihaloC₆₋₁₄arylC₁₋₈alkanyl, haloC₆₋₁₄arylC₁₋₈alkanyl,diC₁₋₈alkanyloxyC₆₋₁₄arylC₁₋₈alkanyl, orC₆₋₁₄aryloxyC₆₋₁₄arylC₁₋₈alkanyl;

(ii) R³ is C₁₋₈alkanylC₆₋₁₄arylC₁₋₈alkanyl, C₆₋₁₄arylC₁₋₈alkanyl,haloC₆₋₁₄arylC₁₋₈alkanyl, C₁₋₈alkanyloxyC₆₋₁₄arylC₁₋₈alkanyl,diC₁₋₈alkanyloxyC₆₋₁₄arylC₁₋₈alkanyl, orC₆₋₁₄aryloxyC₆₋₁₄arylC₁₋₈alkanyl;

(jj) R³ is C₁₋₈alkanylC₆₋₁₄arylC₁₋₈alkanyl, C₆₋₁₄arylC₁₋₈alkanyl,haloC₆₋₁₄arylC₁₋₈alkanyl, C₁₋₈alkanyloxyC₆₋₁₄arylC₁₋₈alkanyl, orC₆₋₁₄aryloxyC₆₋₁₄arylC₁₋₈alkanyl;

(kk) R³ is C₆₋₁₄arylC₁₋₈alkanyl, C₁₋₈alkanyloxyC₆₋₁₄arylC₁₋₈alkanyl,diC₁₋₈alkanyloxyC₆₋₁₄arylC₁₋₈alkanyl, orC₆₋₁₄aryloxyC₆₋₁₄arylC₁₋₈alkanyl;

(ll) R³ is C₁₋₈alkanylC₆₋₁₄arylC₁₋₈alkanyl, C₆₋₁₄arylC₁₋₈alkanyl,haloC₆₋₁₄arylC₁₋₈alkanyl, C₁₋₈alkanyloxyC₆₋₁₄arylC₁₋₈alkanyl, orC₆₋₁₄aryloxyC₆₋₁₄arylC₁₋₈alkanyl;

(mm) R³ is heterocyclicC₁₋₈alkanyl, oxoheterocyclicC₁₋₈alkanyl,C₁₋₈alkanylC₃₋₈cyclicheteroalkanylC₁₋₈alkanyl, C₅₋₁₄heteroaryl, orC₁₋₈alkanylC₆₋₁₄aryl;

(nn) R³ is oxoC₃₋₈cyclicheteroalkanylC₁₋₈alkanyl,C₁₋₈alkanylC₃₋₈cyclicheteroalkanylC₁₋₈alkanyl, C₁₋₈alkanyl, orC₃₋₈cyclicheteroalkanylC₁₋₈alkanyl;

(oo) R³ is C₁₋₈alkanylC₃₋₈cyclicheteroalkanylC₁₋₈alkanyl,C₃₋₈cyclicheteroalkanylC₁₋₈alkanyl, C₁₋₈alkanyl, oroxoC₃₋₈cyclicheteroalkanylC₁₋₈alkanyl;

(pp) R³ is C₁₋₈alkanylC₃₋₈cyclicheteroalkanyl, or C₁₋₈alkanyl;

(qq) R³ is C₁₋₈alkanyloxyC₆₋₁₄arylC₁₋₈alkanyl,oxoC₃₋₈cyclicheteroalkanylC₁₋₈alkanyl,C₆₋₁₄arylC₁₋₈alkanyloxycarbonylaminoalkanyl, C₁₋₈alkanyl,C₆₋₁₄arylC₁₋₈alkanyl, (C₆₋₁₄aryl)(C₁₋₈alkanylaminocarbonyl)C₁₋₈alkanyl,aminosulfonylC₆₋₁₄arylC₁₋₈alkanyl,(C₁₋₈alkanylthio)(aminocarbonyl)alkanyl, C₁₋₈alkanyl, aminoC₁₋₈alkanyl,C₆₋₁₄arylC₁₋₈alkanylheteroalkanyl, C₁₋₈alkanylC₆₋₁₄arylaminoC₁₋₈alkanyl,C₆₋₁₄aryloxyC₁₋₈alkanyl, or C₆₋₁₄aryloxyC₆₋₁₄aryl;

(rr) combinations of (a) through (qq) above.

Thus, exemplary embodiments of the present invention are as describedbelow.

One embodiment of the present invention is a method of synthesizing ahydroxyethlamino amide of Formula (I) wherein

R¹ is optionally substituted phenyl;

R² is C₆₋₁₄arylC₁₋₈alkanyl, diC₆₋₁₄arylC₁₋₈alkanyl, C₁₋₈alkanyl,alkenyl, hydrogen, or N-linked-C₁₋₈alkanylcarbonylamino; and

R³ is optionally substituted C₁₋₈alkanyl.

Another embodiment of the present invention is a method of synthesizinga hydroxyethlamino amide of Formula (I) wherein

R¹ is optionally substituted pyridyl and pyrazinyl, quinolyl, or furyl;

R² is hydrogen, C₁₋₈alkanyloxyC₆₋₁₄arylC₁₋₈alkanyl, orC₁₋₈alkanylC₆₋₁₄arylC₁₋₈alkanyl; and

R³ is optionally substituted C₁₋₈alkanyl.

Another embodiment of the present invention is a method of synthesizinga hydroxyethlamino amide of Formula (I) wherein

R¹ is C₁₋₈alkanylC₆₋₁₄aryl, C₆₋₁₄arylC₁₋₈alkanyl, ordiC₁₋₈alkanyloxyC₆₋₁₄aryl;

R² is hydrogen, C₁₋₈alkanyl, C₅₋₁₄heteroarylC₁₋₈alkanyl,C₆₋₁₄arylC₁₋₈alkanyl; and

R³ is heterocyclicC₁₋₈alkanyl, oxoheterocyclicC₁₋₈alkanyl,C₁₋₈alkanylC₃₋₈cyclicheteroalkanylC₁₋₈alkanyl, C₅₋₁₄heteroaryl, orC₁₋₈alkanylC₆₋₁₄aryl.

Another embodiment of the present invention is a method of synthesizinga hydroxyethlamino amide of Formula (I) wherein

R¹ is C₁₋₈alkanylC₆₋₁₄aryl, C₆₋₁₄arylC₁₋₈alkanyl, ordiC₁₋₈alkanyloxyC₆₋₁₄aryl;

R² is hydrogen, C₁₋₈alkanyl, C₅₋₁₄heteroarylC₁₋₈alkanyl,C₆₋₁₄arylC₁₋₈alkanyl; and

R³ is R³ is C₁₋₈alkanylC₃₋₈cyclicheteroalkanyl, or C₁₋₈alkanyl.

Another embodiment of the present invention is directed to compositionscomprising a compound of Formula (I). In on embodiment, such compoundsare those of Formula (I) wherein said compound is selected from thegroup consisting of:

a compound of formula (I) wherein R¹ is 4-(phenylmethyl)phenyl, R² is H,and R³ is 4-methoxyphenylmethyl;

a compound of formula (I) wherein R¹ is 4-(phenylmethyl)phenyl, R² is3-methylbut-1-yl, and R³ is 4-methoxyphenylmethyl;

a compound of formula (I) wherein R¹ is 4-(phenylmethyl)phenyl, R² isfuran-2-yl, and R³ is 4-methoxyphenylmethyl;

a compound of formula (I) wherein R¹ is 4-(phenylmethyl)phenyl, R² is2-phenyleth-1-yl, and R³ is 3-(1-pyrrolidin-2-one_prop-1yl;

a compound of formula (I) wherein R¹ is 4-(phenylmethyl)phenyl, R² is3-methylbut-1-yl, and R³ is 3-(1-pyrrolidin-2-one_prop-1yl;

a compound of formula (I) wherein R¹ is 4-(phenylmethyl)phenyl, R² is2-phenyleth-1-yl, and R³ is (2-((phenylmethoxycarbonyl)-amino)eth-1-yl);

a compound of formula (I) wherein R¹ is 4-(phenylmethyl)phenyl, R² is3-methylbut-1-yl, and R³ is (2-((phenylmethoxycarbonyl)-amino)eth-1-yl);

a compound of formula (I) wherein R¹ is 3-methoxyphenyl, R² is2-phenyleth-1-yl, and R³ is 3-(1-pyrrolidin-2-one_prop-1yl;

a compound of formula (I) wherein R¹ is 3-methoxyphenyl, R² is3-methylbut-1-yl, and R³ is 3-(1-pyrrolidin-2-one_prop-1yl;

a compound of formula (I) wherein R¹ is 3-methoxyphenyl, R² is2-phenyleth-1-yl, and R³ is (2-((phenylmethoxycarbonyl)-amino)eth-1-yl);

a compound of formula (I) wherein R¹ is 3-methoxyphenyl, R² is3-methylbut-1-yl, and R³ is (2-((phenylmethoxycarbonyl)-amino)eth-1-yl);

a compound of formula (I) wherein R¹ is 3-methylphenyl, R² is2-phenyleth-1-yl, and R³ is 3-(1-pyrrolidin-2-one_prop-1yl;

a compound of formula (I) wherein R¹ is 3-methylphenyl, R² is3-methylbut-1-yl, and R³ is 3-(1-pyrrolidin-2-one_prop-1yl;

a compound of formula (I) wherein R¹ is 3-methylphenyl, R² is2-phenyleth-1-yl, and R³ is (2-((phenylmethoxycarbonyl)-amino)eth-1-yl);

a compound of formula (I) wherein R¹ is 3-methylphenyl, R² is3-methylbut-1-yl, and R³ is (2-((phenylmethoxycarbonyl)-amino)eth-1-yl);

a compound of formula (I) wherein R¹ is 4-(phenylmethoxy)phenyl, R² is2-phenyleth-1-yl, and R³ is 3-(1-pyrrolidin-2-one_prop-1yl;

a compound of formula (I) wherein R¹ is 4-(phenylmethoxy)phenyl, R² is3-methylbut-1-yl, and R³ is 3-(1-pyrrolidin-2-one_prop-1yl;

a compound of formula (I) wherein R¹ is 4-(phenylmethoxy)phenyl, R² is2-phenyleth-1-yl, and R³ is (2-((phenylmethoxycarbonyl)-amino)eth-1-yl);

a compound of formula (I) wherein R¹ is 4-(phenylmethoxy)phenyl, R² is3-methylbut-1-yl, and R³ is (2-((phenylmethoxycarbonyl)-amino)eth-1-yl);

a compound of formula (I) wherein R¹ is 4-(phenylmethyl)phenyl, R² is2-phenyleth-1-yl, and R³ is cyclohexyl;

a compound of formula (I) wherein R¹ is 4-(phenylmethyl)phenyl, R² is3-methylbut-1-yl, and R³ is cyclohexyl;

a compound of formula (I) wherein R¹ is 4-(phenylmethyl)phenyl, R² is2-phenyleth-1-yl, and R³ is cyclohexylmethyl;

a compound of formula (I) wherein R¹ is 4-(phenylmethyl)phenyl, R² is3-methylbut-1-yl, and R³ is cyclohexylmethyl;

a compound of formula (I) wherein R¹ is 4-(phenylmethyl)phenyl, R² is2-phenyleth-1-yl, and R³ is 2-phenyleth-1-yl;

a compound of formula (I) wherein R¹ is 4-(phenylmethyl)phenyl, R² is3-methylbut-1-yl, and R³ is 2-phenyleth-1-yl;

a compound of formula (I) wherein R¹ is 4-(phenylmethyl)phenyl, R² is3-methylbut-1-yl, and R³ is1-(cyclohexylaminocarbonyl)-2-(phenylmethyl);

a compound of formula (I) wherein R¹ is 4-(phenylmethyl)phenyl, R² is2-phenyleth-1-yl, and R³ is 2-(4-sulfamoylphenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is 4-(phenylmethyl)phenyl, R² is3-methylbut-1-yl, and R³ is 2-(4-sulfamoylphenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is 3-methoxyphenyl, R² is3-methylbut-1-yl, and R³ is 4-methylthiobutanamid-2-yl;

a compound of formula (I) wherein R¹ is 3-methoxyphenyl, R² is2-phenyleth-1-yl, and R³ is cyclohexyl;

a compound of formula (I) wherein R¹ is 3-methoxyphenyl, R² is3-methylbut-1-yl, and R³ is cyclohexyl;

a compound of formula (I) wherein R¹ is 3-methoxyphenyl, R² is2-phenyleth-1-yl, and R³ is cyclohexylmethyl;

a compound of formula (I) wherein R¹ is 3-methoxyphenyl, R² is3-methylbut-1-yl, and R³ is cyclohexylmethyl;

a compound of formula (I) wherein R¹ is 3-methoxyphenyl, R² is2-phenyleth-1yl, and R³ is 2-phenyleth-1-yl;

a compound of formula (I) wherein R¹ is 3-methoxyphenyl, R² is3-methylbut-1-yl, and R³ is 2-phenyleth-1-yl;

a compound of formula (I) wherein R¹ is 3-methoxyphenyl, R² is2-phenyleth-1-yl, and R³ is N-cyclohexyl-3-phenylpropanamide-2-yl;

a compound of formula (I) wherein R¹ is 3-methoxyphenyl, R² is3-methylbut-1-yl, and R³ is N-cyclohexyl-3-phenylpropanamide-2-yl;

a compound of formula (I) wherein R¹ is 3-methoxyphenyl, R² is2-phenyleth-1-yl, and R³ is 2-(4-sulfamoylphenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is 3-methoxyphenyl, R² is3-methylbut-1-yl, and R³ is 2-(4-sulfamoylphenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is 3-methoxyphenyl, R² is2-phenyleth-1-yl, and R³ is (2-((phenylmethoxycarbonyl)-amino)eth-1-yl);

a compound of formula (I) wherein R¹ is 3-methoxyphenyl, R² is3-methylbut-1-yl, and R³ is (2-((phenylmethoxycarbonyl)-amino)eth-1-yl);

a compound of formula (I) wherein R¹ is 3-methoxyphenyl, R² is2-phenyleth-1-yl, and R³ is 2-aminoeth-1-yl;

a compound of formula (I) wherein R¹ is 3-methoxyphenyl, R² is3-methylbut-1-yl, and R³ is 2-aminoeth-1-yl;

a compound of formula (I) wherein R¹ is 4-(phenylmethyl)phenyl, R² is3-methylbut-1-yl, and R³ is (2-((phenylmethoxycarbonyl)-amino)eth-1-yl);

a compound of formula (I) wherein R¹ is 4-(phenylmethyl)phenyl, R² is2-phenyleth-1-yl, and R³ is 2-aminoeth-1-yl;

a compound of formula (I) wherein R¹ is 4-(phenylmethyl)phenyl, R² is3-methylbut-1-yl, and R³ is 2-aminoeth-1-yl;

a compound of formula (I) wherein R¹ is 4-methylphenyl, R² is3-methylbut-1-yl, and R³ is 2-(4-methylphenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is 4-methylphenyl, R² is3-methylbut-1-yl, and R³ is 2-phenyleth-1-yl;

a compound of formula (I) wherein R¹ is 4-methylphenyl, R² is3-methylbut-1-yl, and R³ is 2-(3-fluorophenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is 4-methylphenyl, R² is3-methylbut-1-yl, and R³ is 2-(3-methoxyphenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is 4-methylphenyl, R² is3-methylbut-1-yl, and R³ is 2-(3,5-dimethoxyphenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is 4-methylphenyl, R² is3-methylbut-1-yl, and R³ is 2-(4-phenoxyphenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is 4-methylphenyl, R² is2-phenyleth-1-yl, and R³ is 2-(4-methylphenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is 4-methylphenyl, R² is2-phenyleth-1-yl, and R³ is 2-phenyleth-1-yl;

a compound of formula (I) wherein R¹ is 4-methylphenyl, R² is2-phenyleth-1-yl, and R³ is 2-(3-fluorophenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is 4-methylphenyl, R² is2-phenyleth-1-yl, and R³ is 2-(3-methoxyphenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is 4-methylphenyl, R² is2-phenyleth-1-yl, and R³ is 2-(3,5-dimethoxyphenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is 4-methylphenyl, R² is2-phenyleth-1-yl, and R³ is 2-(4-phenoxyphenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is phenylmethyl, R² is3-methylbut-1-yl, and R³ is 2-(3-fluorophenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is phenylmethyl, R² is3-methylbut-1-yl, and R³ is 2-(3-methoxyphenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is phenylmethyl, R² is3-methylbut-1-yl, and R³ is 2-(3,5-dimethoxyphenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is phenylmethyl, R² is3-methylbut-1-yl, and R³ is 2-(4-phenoxyphenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is phenylmethyl, R² is2-phenyleth-1-yl, and R³ is 2-(3-methoxyphenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is phenylmethyl, R² is2-phenyleth-1-yl, and R³ is 2-(3,5-dimethoxyphenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is phenylmethyl, R² is2-phenyleth-1-yl, and R³ is 2-(4-phenoxyphenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is 3,5-dimethoxyphenyl, R² is3-methylbut-1-yl, and R³ is 2-(3,5-dimethoxyphenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is 3-(dimethylamino)phenyl, R² is3-methylbut-1-yl, and R³ is 2-(3,4-dichlorophenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is 3-(dimethylamino)phenyl, R² is3-methylbut-1-yl, and R³ is 2-(3-fluorophenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is 3-(dimethylamino)phenyl, R² is3-methylbut-1-yl, and R³ is 2-(3-methoxyphenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is 3-(dimethylamino)phenyl, R² is3-methylbut-1-yl, and R³ is 2-(3,5-dimethoxyphenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is 3-(dimethylamino)phenyl, R² is3-methylbut-1-yl, and R³ is 2-(4-phenoxyphenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is 3-(dimethylamino)phenyl, R² is2-phenyleth-1-yl, and R³ is 2-(3,4-dichlorophenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is 3-(dimethylamino)phenyl, R² is2-phenyleth-1-yl, and R³ is 2-(3-fluorophenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is 4-acetylphenyl, R² is3-methylbut-1-yl, and R³ is 2-(3,4-dichlorophenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is 4-acetylphenyl, R² is3-methylbut-1-yl, and R³ is 2-phenyleth-1-yl;

a compound of formula (I) wherein R¹ is 4-acetylphenyl, R² is3-methylbut-1-yl, and R³ is 2-(3-fluorophenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is 4-acetylphenyl, R² is3-methylbut-1-yl, and R³ is 2-(3-methoxyphenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is 4-acetylphenyl, R² is3-methylbut-1-yl, and R³ is 2-(4-phenoxyphenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is 4-acetylphenyl, R² is2-phenyleth-1-yl, and R³ is 2-(3,4-dichlorophenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is 4-acetylphenyl, R² is2-phenyleth-1-yl, and R³ is 2-phenyleth-1-yl;

a compound of formula (I) wherein R¹ is 4-acetylphenyl, R² is2-phenyleth-1-yl, and R³ is 2-(3-methoxyphenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is 4-acetylphenyl, R² is2-phenyleth-1-yl, and R³ is 2-(3,5-dimethoxyphenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is 4-acetylphenyl, R² is2-phenyleth-1-yl, and R³ is 2-(4-phenoxyphenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is 3-trifluoromethylphenyl, R² is3-methylbut-1-yl, and R³ is 2-(3,4-dichlorophenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is 3-trifluoromethylphenyl, R² is3-methylbut-1-yl, and R³ is 2-phenyleth-1-yl;

a compound of formula (I) wherein R¹ is 3-trifluoromethylphenyl, R² is3-methylbut-1-yl, and R³ is 2-(3-methoxyphenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is 3-trifluoromethylphenyl, R² is3-methylbut-1-yl, and R³ is 2-(3,5-dimethoxyphenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is 2-chloropyrid-4-yl, R² is3-methylbut-1-yl, and R³ is 2-(3,4-dichlorophenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is 2-chloropyrid-4-yl, R² is3-methylbut-1-yl, and R³ is 2-phenyleth-1-yl;

a compound of formula (I) wherein R¹ is 2-chloropyrid-4-yl, R² is3-methylbut-1-yl, and R³ is 2-(3-fluorophenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is 2-chloropyrid-4-yl, R² is3-methylbut-1-yl, and R³ is 2-(3-methoxyphenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is 2-chloropyrid-4-yl, R² is3-methylbut-1-yl, and R³ is 2-(3,5-dimethoxyphenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is 2-chloropyrid-4-yl, R² is3-methylbut-1-yl, and R³ is 2-(4-ethylphenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is 2-chloropyrid-4-yl, R² is2-phenyleth-1-yl, and R³ is 2-(3,4-dichlorophenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is 2-chloropyrid-4-yl, R² is2-phenyleth-1-yl, and R³ is 2-phenyleth-1-yl;

a compound of formula (I) wherein R¹ is 2-chloropyrid-4-yl, R² is2-phenyleth-1-yl, and R³ is 2-(3-fluorophenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is 2-chloropyrid-4-yl, R² is2-phenyleth-1-yl, and R³ is 2-(3-methoxyphenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is 2-chloropyrid-4-yl, R² is2-phenyleth-1-yl, and R³ is 2-(3,5-dimethoxyphenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is 2-chloropyrid-4-yl, R² is2-phenyleth-1-yl, and R³ is 2-(4-ethylphenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is pyrid-3-yl, R² is3-methylbut-1-yl, and R³ is 2-(3,4-dichlorophenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is pyrid-3-yl, R² is3-methylbut-1-yl, and R³ is 2-phenyleth-1-yl;

a compound of formula (I) wherein R¹ is pyrid-3-yl, R² is3-methylbut-1-yl, and R³ is 2-(3-fluorophenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is pyrid-3-yl, R² is3-methylbut-1-yl, and R³ is 2-(3,5-dimethoxyphenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is pyrid-3-yl, R² is3-methylbut-1-yl, and R³ is 2-(4-ethylphenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is pyrid-3-yl, R² is2-phenyleth-1-yl, and R³ is 2-(3,4-dichlorophenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is pyrid-3-yl, R² is2-phenyleth-1-yl, and R³ is 2-phenyleth-1-yl;

a compound of formula (I) wherein R¹ is pyrid-3-yl, R² is2-phenyleth-1-yl, and R³ is 2-(3-fluorophenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is pyrid-3-yl, R² is2-phenyleth-1-yl, and R³ is 2-(3-methoxyphenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is pyrid-3-yl, R² is2-phenyleth-1-yl, and R³ is 2-(3,5-dimethoxyphenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is pyrid-3-yl, R² is2-phenyleth-1-yl, and R³ is 2-(4-ethylphenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is pyrazin-2-yl, R² is3-methylbut-1-yl, and R³ is 2-(3,4-dichlorophenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is pyrazin-2-yl, R² is3-methylbut-1-yl, and R³ is 2-phenyleth-1-yl;

a compound of formula (I) wherein R¹ is pyrazin-2-yl, R² is3-methylbut-1-yl, and R³ is 2-(3-fluorophenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is pyrazin-2-yl, R² is3-methylbut-1-yl, and R³ is 2-(3-methoxyphenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is pyrazin-2-yl, R² is3-methylbut-1-yl, and R³ is 2-(3,5-dimethoxyphenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is pyrazin-2-yl, R² is3-methylbut-1-yl, and R³ is 2-(4-ethylphenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is pyrazin-2-yl, R² is2-phenyleth-1-yl, and R³ is 2-(3,4-dichlorophenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is pyrazin-2-yl, R² is2-phenyleth-1-yl, and R³ is 2-phenyleth-1-yl;

a compound of formula (I) wherein R¹ is 3-quinolyl, R² is butyl, and R³is 2-(morpholin-4-yl)prop-3-yl;

a compound of formula (I) wherein R¹ is 3-quinolyl, R² is butyl, and R³is 2-(2-pyridyl)eth-1yl;

a compound of formula (I) wherein R¹ is 3-quinolyl, R² is butyl, and R³is 2-(2-thieny)eth-1yl;

a compound of formula (I) wherein R¹ is 3-quinolyl, R² is butyl, and R³is 2-(1-pyrrolidin-2-one_eth-1yl;

a compound of formula (I) wherein R¹ is 3-quinolyl, R² is butyl, and R³is 2-(2-methyl-1-piperidinyl)eth-1-yl;

a compound of formula (I) wherein R¹ is 3-quinolyl, R² is butyl, and R³is 2-(4-ethylphenyl)eth-1-yl ;

a compound of formula (I) wherein R¹ is 3-quinolyl, R² is3-methylbut-1-yl, and R³ is 2-(morpholin-4-yl)prop-3-yl;

a compound of formula (I) wherein R¹ is 3-quinolyl, R² is3-methylbut-1-yl, and R³ is 2-(2-pyridyl)eth-1yl;

a compound of formula (I) wherein R¹ is 3-quinolyl, R² is3-methylbut-1-yl, and R³ is 2-(2-thienyl)eth-1yl;

a compound of formula (I) wherein R¹ is 3-quinolyl, R² is3-methylbut-1-yl, and R³ is 2-(2-methyl-1-piperidinyl)eth-1-yl;

a compound of formula (I) wherein R¹ is 3-quinolyl, R² is3-methylbut-1-yl, and R³ is 2-(4-ethylphenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is cyclohexyl, R² is butyl, and R³is 2-(2-pyridyl)eth-1yl;

a compound of formula (I) wherein R¹ is cyclohexyl, R² is butyl, and R³is 2-(2-thienyl)eth-1yl;

a compound of formula (I) wherein R¹ is cyclohexyl, R² is butyl, and R³is 2-(2-methyl-1-piperidinyl)eth-1-yl;

a compound of formula (I) wherein R¹ is cyclohexyl, R² is butyl, and R³is 2-(4-ethylphenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is cyclohexyl, R² is3-methylbut-1-yl, and R³ is 2-(2-pyridyl)eth-1yl;

a compound of formula (I) wherein R¹ is cyclohexyl, R² is3-methylbut-1-yl, and R³ is 2-(2-thienyl)eth-1yl;

a compound of formula (I) wherein R¹ is cyclohexyl, R² is3-methylbut-1-yl, and R³ is 2-(1-pyrrolidin-2-one_eth-1yl;

a compound of formula (I) wherein R¹ is cyclohexyl, R² is3-methylbut-1-yl, and R³ is 2-(2-methyl-1-piperidinyl)eth-1-yl;

a compound of formula (I) wherein R¹ is cyclohexyl, R² is3-methylbut-1-yl, and R³ is 2-(4-ethylphenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is methylthiomethyl, R² is butyl,and R³ is 2-(morpholin-4-yl)prop-3-yl;

a compound of formula (I) wherein R¹ is methylthiomethyl, R² is butyl,and R³ is 2-(2-pyridyl)eth-1yl;

a compound of formula (I) wherein R¹ is methylthiomethyl, R² is butyl,and R³ is 2-(2-thienyl)eth-1yl;

a compound of formula (I) wherein R¹ is methylthiomethyl, R² is butyl,and R³ is 2-(1-pyrrolidin-2-one_eth-1yl;

a compound of formula (I) wherein R¹ is methylthiomethyl, R² is butyl,and R³ is 2-(2-methyl-1-piperidinyl)eth-1-yl;

a compound of formula (I) wherein R¹ is methylthiomethyl, R² is butyl,and R³ is 2-(4-ethylphenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is methylthiomethyl, R² is3-methylbut-1-yl, and R³ is 2-(morpholin-4-yl)prop-3-yl;

a compound of formula (I) wherein R¹ is methylthiomethyl, R² is3-methylbut-1-yl, and R³ is 2-(2-pyridyl)eth-1yl;

a compound of formula (I) wherein R¹ is methylthiomethyl, R² is3-methylbut-1-yl, and R³ is 2-(2-thienyl)eth-1yl;

a compound of formula (I) wherein R¹ is methylthiomethyl, R² is3-methylbut-1-yl, and R³ is 2-(2-methyl-1-piperidinyl)eth-1-yl;

a compound of formula (I) wherein R¹ is methylthiomethyl, R² is3-methylbut-1-yl, and R³ is 2-(4-ethylphenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is 3-methylfur-2-yl, R² is butyl,and R³ is 2-(morpholin-4-yl)prop-3-yl;

a compound of formula (I) wherein R¹ is 3-methylfur-2-yl, R² is butyl,and R³ is 2-(2-pyridyl)eth-1yl;

a compound of formula (I) wherein R¹ is 3-methylfur-2-yl, R² is butyl,and R³ is 2-(2-thienyl)eth-1yl;

a compound of formula (I) wherein R¹ is 3-methylfur-2-yl, R² is butyl,and R³ is 2-(1-pyrrolidin-2-one_eth-1yl;

a compound of formula (I) wherein R¹ is 3-methylfur-2-yl, R² is butyl,and R³ is 2-(2-methyl-1-piperidinyl)eth-1-yl;

a compound of formula (I) wherein R¹ is 3-methylfur-2-yl, R² is butyl,and R³ is 2-(4-ethylphenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is 3-methylfur-2-yl, R² is3-methylbut-1-yl, and R³ is 2-(morpholin-4-yl)prop-3-yl;

a compound of formula (I) wherein R¹ is 3-methylfur-2-yl, R² is3-methylbut-1-yl, and R³ is 2-(2-pyridyl)eth-1yl;

a compound of formula (I) wherein R¹ is 3-methylfur-2-yl, R² is3-methylbut-1-yl, and R³ is 2-(2-thienyl)eth-1yl;

a compound of formula (I) wherein R¹ is 3-methylfur-2-yl, R² is3-methylbut-1-yl, and R³ is 2-(2-methyl-1-piperidinyl)eth-1-yl;

a compound of formula (I) wherein R¹ is 3-methylfur-2-yl, R² is3-methylbut-1-yl, and R³ is 2-(4-ethylphenyl)eth-1-yl;

a compound of formula (I) wherein R¹ is phenylmethoxy, R² is3-methylbut-1-yl, and R³ is 3-benzoxyphenyl;

a compound of formula (I) wherein R¹ is phenylmethoxy, R² is3-methylbut-1-yl, and R³ is naphth-1-ylmethyl;

a compound of formula (I) wherein R¹ is phenylmethoxy, R² is2-phenyleth-1-yl, and R³ is naphth-1-ylmethyl;

a compound of formula (I) wherein R¹ is phenylmethoxy, R² is3-methylbut-1-yl, and R³ is 1-benzylpiperidin-4-yl;

a compound of formula (I) wherein R¹ is phenylmethoxy, R² is3-methylbut-1-yl, and R³ is 2-(N-(3-methylphenyl)-N-ethylamino)eth-1-yl;

a compound of formula (I) wherein R¹ is phenylmethoxy, R² is2-phenyleth-1-yl, and R³ is 2-(N-(3-methylphenyl)-N-ethylamino)eth-1-yl;

a compound of formula (I) wherein R¹ is phenylmethoxy, R² is3-methylbut-1-yl, and R³ is 2-phenoxyeth-1-yl;

a compound of formula (I) wherein R¹ is phenylmethoxy, R² is2-phenyleth-1-yl, and R³ is 2-phenoxyeth-1-yl;

a compound of formula (I) wherein R¹ is acetamidomethyl, R² is2-phenyleth-1-yl, and R³ is naphth-1-ylmethyl;

a compound of formula (I) wherein R¹ is acetamidomethyl, R² is3-methylbut-1-yl, and R³ is 2-(N-(3-methylphenyl)-N-ethylamino)eth-1-yl;

a compound of formula (I) wherein R¹ is acetamidomethyl, R² is2-phenyleth-1-yl, and R³ is 2-(N-(3-methylphenyl)-N-ethylamino)eth-1-yl;

a compound of formula (I) wherein R¹ is phenylmethoxy, R² is3-methylbut-1-yl, and R³ is 4-phenoxyphenyl;

a compound of formula (I) wherein R¹ is phenylmethoxy, R² is2-phenyleth-1-yl, and R³ is 4-phenoxyphenyl;

a compound of formula (I) wherein R¹ is phenylmethoxy, R² is3-methylbut-1-yl, and R³ is 3-benzoxyphenyl;

a compound of formula (I) wherein R¹ is phenylmethoxy, R² is2-phenyleth-1-yl, and R³ is 3-benzoxyphenyl;

a compound of formula (I) wherein R¹ is phenylmethoxy, R² is3-methylbut-1-yl, and R³ is naphth-1-ylmethyl;

a compound of formula (I) wherein R¹ is phenylmethoxy, R² is2-phenyleth-1-yl, and R³ is naphth-1-ylmethyl;

a compound of formula (I) wherein R¹ is phenylmethoxy, R² is3-methylbut-1-yl, and R³ is 1-benzylpiperidin-4-yl;

a compound of formula (I) wherein R¹ is phenylmethoxy, R² is2-phenyleth-1-yl, and R³ is 1-benzylpiperidin-4-yl;

a compound of formula (I) wherein R¹ is phenylmethoxy, R² is3-methylbut-1-yl, and R³ is 2-(N-(3-methylphenyl)-N-ethylamino)eth-1-yl;

a compound of formula (I) wherein R¹ is phenylmethoxy, R² is2-phenyleth-1-yl, and R³ is 2-(N-(3-methylphenyl)-N-ethylamino)eth-1-yl;

a compound of formula (I) wherein R¹ is phenylmethoxy, R² is3-methylbut-1-yl, and R³ is 2-phenoxyeth-1-yl;

a compound of formula (I) wherein R¹ is phenylmethoxy, R² is2-phenyleth-1-yl, and R³ is 2-phenoxyeth-1-yl;

a compound of formula (I) wherein R¹ is pyran-2-one-4-yl, R² is H, andR³ is 2-(1-pyrrolidin-2-one_eth-1yl;

a compound of formula (I) wherein R¹ is pyran-2-one-4-yl, R² is H, andR³ is cyclopropylmethyl;

a compound of formula (I) wherein R¹ is pyran-2-one-4-yl, R² is H, andR³ is 2-(2-methyl-1-piperidinyl)eth-1-yl;

a compound of formula (I) wherein R¹ is pyran-2-one-4-yl, R² is H, andR³ is cyclohexylmethyl;

a compound of formula (I) wherein R¹ is pyran-2-one-4-yl, R² is H, andR³ is tetrahydrofuran-2-yl;

a compound of formula (I) wherein R¹ is 2-cyclopentyleth-1-yl, R² is H,and R³ is 2-(morpholin-4-yl)prop-3-yl;

a compound of formula (I) wherein R¹ is 2-cyclopentyleth-1-yl, R² is H,and R³ is 2-(2-methyl-1-piperidinyl)eth-1-yl;

a compound of formula (I) wherein R¹ is 2-cyclopentyleth-1-yl, R² is H,and R³ is cyclohexylmethyl;

a compound of formula (I) wherein R¹ is 2-cyclopentyleth-1-yl, R² is4-methoxyphenylmethyl, and R³ is tetrahydrofuran-2-yl;

a compound of formula (I) wherein R¹ is 2-cyclopentyleth-1-yl, R² is4-methoxyphenylmethyl, and R³ is cyclopropylmethyl;

a compound of formula (I) wherein R¹ is 2-cyclopentyleth-1-yl, R² is H,and R³ is tetrahydrofuran-2-yl;

a compound of formula (I) wherein R¹ is 2-cyclopentyleth-1-yl, R² is H,and R³ is cyclopropylmethyl;

a compound of formula (I) wherein R¹ is methysulfonylmethyl, R² is H,and R³ is 3-(2-methyl-1-piperidinyl)prop-1-yl;

a compound of formula (I) wherein R¹ is methysulfonylmethyl, R² is H,and R³ is cyclohexylmethyl;

a compound of formula (I) wherein R¹ is 2-phenylethyn-1-yl, R² is H, andR³ is 2-(morpholin-4-yl)prop-3-yl;

a compound of formula (I) wherein R¹ is 2-phenylethyn-1-yl, R² is H, andR³ is 3-(2-methyl-1-piperidinyl)prop-1-yl;

a compound of formula (I) wherein R¹ is 2-phenylethyn-1-yl, R² is H, andR³ is cyclohexylmethyl;

a compound of formula (I) wherein R¹ is 2-phenylethyn-1-yl, R² is H, andR³ is tetrahydrofuran-2-yl;

a compound of formula (I) wherein R¹ is 2-cyclopentyleth-1-yl, R² is4-isopropylphenylmethyl, and R³ is 3-(1-pyrrolidin-2-one_prop-1yl;

a compound of formula (I) wherein R¹ is 2-cyclopentyleth-1-yl, R² is4-isopropylphenylmethyl, and R³ is 3-(2-methyl-1-piperidinyl)prop-1-yl;

a compound of formula (I) wherein R¹ is 2-cyclopentyleth-1-yl, R² is4-isopropylphenylmethyl, and R³ is cyclohexylmethyl;

a compound of formula (I) wherein R¹ is 2-cyclopentyleth-1-yl, R² is4-isopropylphenylmethyl, and R³ is tetrahydrofuran-2-yl;

a compound of formula (I) wherein R¹ is 2-cyclopentyleth-1-yl, R² is4-isopropylphenylmethyl, and R³ is cyclopropylmethyl;

a compound of formula (I) wherein R¹ is 2-phenylethyn-1-yl, R² is4-methoxyphenylmethyl, and R³ is cyclohexylmethyl;

a compound of formula (I) wherein R¹ is 2-phenylethyn-1-yl, R² is4-methoxyphenylmethyl, and R³ is tetrahydrofuran-2-yl; and

a compound of formula (I) wherein R¹ is 2-phenylethyn-1-yl, R² is4-isopropylphenylmethyl, and R³ is 3-(1-pyrrolidin-2-one_prop-1yl;

The present invention is also directed to a compound of formula (Ia):

wherein (support) is selected from the group consisting of amine basedpolystyrene resins. Preferably, (support) is a Rink type resin, and morepreferably, (support) is a Rink-AM resin.

The present invention is also directed to a compound of formula (Ib):

wherein:

R¹ is C₁₋₈alkanyl, cyclicC₁₋₈alkanyl, C₆₋₁₄aryl, C₅₋₁₄heteroarylC₂₋₈alkenyl, C₁₋₈alkoxy(C₂₋₈)alkenyl, C₂₋₈alkynyl,C₁₋₈alkoxy(C₂₋₈)alkynyl, heteroaryl(C₂₋₈)alkenyl, orheteroaryl(C₂₋₈)alkynyl; wherein said C₁₋₈alkanyl, cyclicC₁₋₈alkanyl,C₆₋₁₄aryl, C₅₋₁₄heteroaryl C₂₋₈alkenyl, C₁₋₈alkoxy(C₂₋₈)alkenyl,C₂₋₈alkynyl, C₁₋₈alkoxy(C₂₋₈)alkynyl, heteroaryl(C₂₋₈)alkenyl, andheteroaryl(C₂₋₈)alkynyl are optionally substituted with one to twosubstituents independently selected from the group consisting ofC₆₋₁₄aryloxy, diC₁₋₈alkanylamino, C₁₋₈alkanylamino, C₁₋₈alkanyl,C₆₋₁₄aryl, C₁₋₈alkanyloxy, C₁₋₈alkanylcarbonyl, perhaloC₁₋₈alkanyl,halo, C₅₋₁₄heteroaryl, C₁₋₈alkanyl, C₁₋₈alkanylthio,oxoC₅₋₈cyclicheteroalkenyl, C₆₋₁₄arylalkynyl, C₁₋₈alkanylsulfonyl,C₆₋₁₄arylC₁₋₈alkanyl, C₁₋₈alkanyloxy, C₆₋₁₄arylC₁₋₈alkanyloxy,C₆₋₁₄arylC₁₋₈alkanyloxycarbonylamino, and C₁₋₈alkanylcarbonylamino; and

wherein (support) is selected from the group consisting of amine basedpolystyrene resins. Preferably, (support) is a Rink type resin, and morepreferably, (support) is a Rink-AM resin.

The compounds of the present invention may also be present in the formof pharmaceutically acceptable salts. For use in medicine, the salts ofthe compounds of this invention refer to non-toxic “pharmaceuticallyacceptable salts” (Ref. International J. Pharm., 1986, 33, 201-217; J.Pharm. Sci., 1997 (January), 66, 1, 1). Other salts well known to thosein the art may, however, be useful in the preparation of compoundsaccording to this invention or of their pharmaceutically acceptablesalts. Representative organic or inorganic acids include, but are notlimited to, hydrochloric, hydrobromic, hydriodic, perchloric, sulfuric,nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic,maleic, fumaric, malic, tartaric, citric, benzoic, mandelic,methanesulfonic, hydroxyethanesulfonic, benzenesulfonic, oxalic, pamoic,2-naphthalenesulfonic, ρ-toluenesulfonic, cyclohexanesulfamic,salicylic, saccharinic or trifluoroacetic acid. Representative organicor inorganic bases include, but are not limited to, basic or cationicsalts such as benzathine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine, procaine, aluminum, calcium, lithium,magnesium, potassium, sodium and zinc.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds that are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound which may not be specificallydisclosed, but which converts to the specified compound in vivo afteradministration to the patient. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

Where the compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. It is to be understood that all such isomers and mixturesthereof are encompassed within the scope of the present invention.Furthermore, some of the crystalline forms for the compounds may existas polymorphs and as such are intended to be included in the presentinvention. In addition, some of the compounds may form solvates withwater (i.e., hydrates) or common organic solvents, and such solvates arealso intended to be encompassed within the scope of this invention.

Where the processes for the preparation of the compounds according tothe invention give rise to mixture of stereoisomers, these isomers maybe separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their component enantiomers by standard techniques, such as theformation of diastereomeric pairs by salt formation with an opticallyactive acid, such as (−)-di-p-toluoyl-d-tartaric acid and/or(+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallizationand regeneration of the free base. The compounds may also be resolved byformation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.Alternatively, the compounds may be resolved using a chiral HPLC column.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991. The protectinggroups may be removed at a convenient subsequent stage using methodsknown from the art.

Even though the compounds of the present invention (including theirpharmaceutically, acceptable salts and pharmaceutically acceptablesolvates) can be administered alone, they will generally be administeredin admixture with a pharmaceutical carrier, excipient or diluentselected with regard to the intended route of administration andstandard pharmaceutical or veterinary practice. Thus, the presentinvention is directed to pharmaceutical and veterinary compositionscomprising compounds of Formula (I) and one or more pharmaceuticallyacceptable carriers, excipients or diluents.

By way of example, in the pharmaceutical and veterinary compositions ofthe present invention, the compounds of the present invention may beadmixed with any suitable binder(s), lubricant(s), suspending agent(s),coating agent(s), and/or solubilising agent(s).

Tablets or capsules of the compounds may be administered singly or twoor more at a time, as appropriate. It is also possible to administer thecompounds in sustained release formulations.

Alternatively, the compounds of the general Formula (I) can beadministered by inhalation or in the form of a suppository or pessary,or they may be applied topically in the form of a lotion, solution,cream, ointment or dusting powder. An alternative means of transdermaladministration is by use of a skin patch. For example, they can beincorporated into a cream consisting of an aqueous emulsion ofpolyethylene glycols or liquid paraffin. They can also be incorporated,at a concentration of between 1 and 10% by weight, into an ointmentconsisting of a white wax or white soft paraffin base together with suchstabilizers and preservatives as may be required.

For some applications, preferably the compositions are administeredorally in the form of tablets containing excipients such as starch orlactose, or in capsules or ovules either alone or in admixture withexcipients, or in the form of elixirs, solutions or suspensionscontaining flavoring or coloring agents.

The compositions (as well as the compounds alone) can also be injectedperenterally, for example intracavernosally, intravenously,intramuscularly or subcutaneously. In this case, the compositions willcomprise a suitable carrier or diluent.

For parenteral administration, the compositions are best used in theform of a sterile aqueous solution which may contain other substances,for example enough salts or monosaccharides to make the solutionisotonic with blood.

For buccal or sublingual administration the compositions may beadministered in the form of tablets or lozenges which can be formulatedin a conventional manner.

By way of further example, pharmaceutical and veterinary compositionscontaining one or more of the compounds of the invention describedherein as the active ingredient can be prepared by intimately mixing thecompound or compounds with a pharmaceutical carrier according toconventional pharmaceutical compounding techniques. The carrier may takea wide variety of forms depending upon the desired route ofadministration (e.g., oral, parenteral). Thus for liquid oralpreparations such as suspensions, elixirs and solutions, suitablecarriers and additives include water, glycols, oils, alcohols, flavoringagents, preservatives, stabilizers, coloring agents and the like; forsolid oral preparations, such as powders, capsules and tablets, suitablecarriers and additives include starches, sugars, diluents, granulatingagents, lubricants, binders, disintegrating agents and the like. Solidoral preparations may also be coated with substances such as sugars orbe enteric-coated so as to modulate the major site of absorption. Forparenteral administration, the carrier will usually consist of sterilewater and other ingredients may be added to increase solubility orpreservation. Injectable suspensions or solutions may also be preparedutilizing aqueous carriers along with appropriate additives.

Advantageously, compounds of the present invention may be administeredin a single daily dose, or the total daily dosage may be administered individed doses of two, three or four times daily. Furthermore, compoundsfor the present invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal skinpatches well known to those skilled in that art. To be administered inthe form of a transdermal delivery system, the dosage administrationwill, of course, be continuous rather than intermittent throughout thedosage regimen.

A therapeutically effective amount for use of the instant compounds or apharmaceutical composition thereof comprises a dose range of from about0.01 mg to about 15,000 mg, in particular from about 1 mg to about 5000mg or, more particularly from about 500 mg to about 4000 mg of activeingredient per day for an average (70 kg) human.

For oral administration, a pharmaceutical composition is preferablyprovided in the form of tablets containing, 0.01, 10.0, 50.0, 100, 150,200, 250 and 500 milligrams of the active ingredient for the symptomaticadjustment of the dosage to the subject to be treated.

It is also apparent to one skilled in the art that the therapeuticallyeffective dose for active compounds of the invention or a pharmaceuticalcomposition thereof will vary according to the desired effect.Therefore, optimal dosages to be administered may be readily determinedand will vary with the particular compound used, the mode ofadministration, the strength of the preparation, and the advancement ofthe disease condition. In addition, factors associated with theparticular subject being treated, including subject age, weight, dietand time of administration, will result in the need to adjust the doseto an appropriate therapeutic level. The above dosages are thusexemplary of the average case. There can, of course, be individualinstances where higher or lower dosage ranges are merited, and such arewithin the scope of this invention.

Compounds of this invention may be administered in any of the foregoingcompositions and dosage regimens or by means of those compositions anddosage regimens established in the art whenever use of the compounds ofthe invention as analgesics or anti-pyretics is required for a subjectin need thereof.

The invention also provides a pharmaceutical or veterinary pack or kitcomprising one or more containers filled with one or more of theingredients of the pharmaceutical and veterinary compositions of theinvention. Optionally associated with such container(s) can be a noticein the form prescribed by a governmental agency regulating themanufacture, use or sale of pharmaceuticals or biological products,which notice reflects approval by the agency of manufacture, use or salefor human administration.

The compounds of Formulas (I) and (II) are useful in methods fortreating a disease or condition in a mammal characterized by inadequateactivity of aspartyl proteases. Such methods comprises administering toa mammal in need of such treatment a therapeutically effective amount ofa compound, salt or solvate of Formulas (I) or (II). Such diseases andconditions include Alzheimer's disease and HIV/AIDS.

GENERAL SYNTHETIC METHODS

Representative compounds of the present invention can be synthesized inaccordance with the general synthetic methods described below and areillustrated in the schemes that follows. Since the schemes are anillustration, the invention should not be construed as being limited bythe chemical reactions and conditions expressed. The preparation of thevarious starting materials used in the schemes is well within the skillof persons versed in the art.

The aminohydroxyalkylamides of formula (I) that comprise this inventionare synthesized using the general chemical methods shown in Scheme I.

Abbreviations

Fmoc=9-fluorenylmethoxycarbonyl

DCM=dichloromethane

DCE=dichloroethane

Generation of the Epoxyalkyl Support

Fmoc support is deprotected in a peptide synthesis vessel agitation twotimes for 15-45 min with 25% piperidine/DMF (or other equivalent means,e.g. NMP). Following this agitation, the support is washed successivelywith DCM then MeOH, followed by DCM. Following deprotection DCM anddiisopropylethyl amine are added, followed by 5 equivalent ofdiallylpyrocarbonate. The mixture is agitated and vented for 12-18hours. The solution is then drained and the support washed with DCM thenMeOH (3 cycles), followed by DCM (3×). The support is then washed withdry THF (or other equivalent solvents, e.g. ethyl ether, dioxane) (2×)and then dry THF (or other equivalent solvents, e.g. ethyl ether,dioxane) is added to the reaction vessel, followed by 10-20 equivalentsof Li t-BuO (or other equivalent reagents, e.g. K t-BuO). The mixture isthen agitated for 3-6 hours and drained carefully to ensure the supportremains wet. 15-30 equivalents of epichlorohydrin in DMSO (or otherequivalent solvents, e.g. DMF, DMA, NMP) is then added to the support.The mixture is agitated for 20 hours, the solution is drained, and thesupport is washed with DCM then MeOH (3 cycles), followed by DCM (333 ).The resulting support is then dried under vacuum.

Generation of the Aminohydroxyalkylamides

6-108 equivalents of PhSiH₃ in DCE (or other equivalent solvents, e.g.DCM, chloroform) was added to the epoxyalkyl support. The solution isbubbled with nitrogen and then 0.1-1 equivalents of Pd(PPh₃)₄ is added.The reaction mixture is bubbled with nitrogen for 2-4 h then thesolution is drained and the support washed with DCM then MeOH (3cycles), followed by DCM (3×). The resulting support is dried undervacuum. The support is then taken up in DCE (or other equivalentsolvents, e.g. DCM, chloroform) and 3.5 equivalents of the R¹ carboxylicacid or acid derivative (R¹COY wherein Y is OH, CI, Br, OC₁₋₃alkanyl orOOCR¹) is added in 50% DCE (or other equivalent solvents, e.g. DCM,chloroform)/diisopropylethyl amine, followed by 4.5 equivalents of2-chloro-1,3-dimethylimidazolidinium chloride in DCM (or otherequivalent solvents, e.g. DCM, chloroform). The reaction mixture isagitated for 12-20 hours, the solution is drained, and the support iswashed with DCM then MeOH (3 cycles), followed by DCM (3×). To thesupport from step E was added DCE (or other equivalent solvents, e.g.DCM, chloroform) (2 mL), R²NH₂ and LiClO₄ in ethyl ether. The reactionwas agitated for 18-22 hours. The solution was drained and the supportwashed with DCM then MeOH (3 cycles), followed by DCM (3×).

To the support from step F was added DCE (or other equivalent solvents,e.g. DCM, chloroform), R³CHO, trimethyl orthoformate, and Na(OAc)₃BH inDMF (or other equivalent solvents, e.g. NMP). The reaction was agitatedfor 12-18 hours. The solution was drained and the support was washedwith DCM then MeOH (3 cycles), followed by DCM (3×).

Cleaving the Aminohydroxyalkylamides From The Support To the supportfrom step G was added 50% TFA/DCM. The support was agitated for 60-120minutes and the filtrate collected. The support was washed with 2%TFA/DCM (2 ×). The combined filtrates were concentrated to a residue andpurified by reverse-phase chromatography to furnish the product.

The epoxyalkyl support is generated in accordance with the procedures inScheme 1.

Step 2A:

The support is then taken up in DCE (or other equivalent solvents, e.g.DCM, chloroform) and 3.5 equivalents of the R¹ carboxylic acid or acidderivative (R¹COY wherein Y is OH, Cl, Br, OC₁₋₃alkanyl or OOCR¹) isadded in 50% DCE (or other equivalent solvents, e.g. DCM,chloroform)/diisopropylethyl amine, followed by 4.5 equivalents of2-chloro-1,3-dimethylimidazolidinium chloride in DCM (or otherequivalent solvents, e.g. DCM, chloroform). The reaction mixture isagitated for 12-20 hours, the solution is drained, and the support iswashed with DCM then MeOH (3 cycles), followed by DCM (3×).

Step 2B:

To the support from step 2A was added DCE (or other equivalent solvents,e.g. DCM, chloroform) (2 mL), R²R³NH and LiClO₄ in ethyl ether. Thereaction was agitated for 18-22 hours. The solution was drained and thesupport washed with DCM then MeOH (3 cycles), followed by DCM (3×).

Step 2C:

To the support from step 2B was added 50% TFA/DCM. The support wasagitated for 60-120 minutes and the filtrate collected. The support waswashed with 2% TFA/DCM (2 ×). The combined filtrates were concentratedto a residue and purified by reverse-phase chromatography to furnish theproduct.

The structures of the final products are confirmed by spectroscopic,spectrometric and analytical methods including nuclear magneticresonance (NMR), mass spectrometry (MS) and liquid chromatography(HPLC). In the descriptions for the preparation of compounds of thisinvention, ethyl ether, tetrahydrofuran and dioxane are common examplesof an ethereal solvent; benzene, toluene, hexanes and cyclohexane aretypical hydrocarbon solvents and dichloromethane and dichloroethane arerepresentative halogenhydrocarbon solvents. In those cases where theproduct is isolated as the acid addition salt the free base may beobtained by techniques known to those skilled in the art. In those casesin which the product is isolated as an acid addition salt, the salt maycontain one or more equivalents of the acid.

Representative compounds of the present invention can be synthesized inaccordance with the general synthetic methods and schemes describedabove and are illustrated more particularly below. Since the scheme isan illustration, the invention should not be construed as being limitedby the chemical reactions and conditions expressed. The preparation ofthe various starting materials used in the schemes is well within theskill of persons versed in the art.

Example 1

-   quinoline-3-carboxylic    acid{3-[butyl-(3-morpholin-4-yl-propyl)-amino]-2-hydroxy-propyl}amide

Step A:

To a peptide synthesis vessel was added 25 g Rink-AM resin (Novabiochem200-400 mesh; 0.63 mmol/g loading) and 25% piperidine/DMF (250 mL). Themixture was agitated for 15 min and the solution drained. Once again,25% piperidine/DMF (250 mL) was added and the mixture was agitated for30 min. The solution was drained and the resin washed with DCM then MeOH(3 cycles), followed by DCM (3×).

Step B:

To the resin from step A was added DCM (250 mL) and diisopropylethylamine (10.2 g, 79 mmol), followed by diallylpyrocarbonate (14.7 g, 79mmol). The mixture was agitated and vented for 18 h. The solution wasdrained and the resin washed with DCM then MeOH (3 cycles), followed byDCM (3×).

Step C:

The resin from step B was washed with dry THF (2×) and then dry THF (250mL) was added, followed by Li t-BuO (25.2 g, 0.32 mol). The mixture wasagitated for 4 h and then drained carefully to ensure the resin remainswet. To the resin was added DMSO (250 mL) and epichlorohydrin (43.5 g,0.47 mol). The mixture was agitated for 20 h. The solution was drainedand the resin washed with DCM then MeOH (3 cycles), followed by DCM(3×). The resulting resin was dried under vacuum.

Step D:

To the resin (12 g, 7.5 mmol) from step C was added DCE (120 mL) andPhSiH₃ (6.5 g, 60 mmol). The solution was bubbled with nitrogen and thenPd(PPh₃)₄ (1.75 g, 1.51 mmol) was added. The reaction mixture wasbubbled with nitrogen for 2 h. The solution was drained and the resinwashed with DCM then MeOH (3 cycles), followed by DCM (3×). Theresulting resin was dried under vacuum.

Step E:

To a reaction vessel was added resin (200 mg, 0.14 mmol) from step D,DCE (1 mL), and 3-quinolinecarboxylic acid (86 mg, 0.50 mmol) in 50%DCE/diisopropylethyl amine (0.5 mL), followed by2-chloro-1,3-dimethylimidazolidinium chloride (106 mg, 0.63 mmol) in DCM(0.5 mL). The reaction mixture was agitated for 22 h. The solution wasdrained and the resin washed with DCM then MeOH (3 cycles), followed byDCM (3×).

Step F:

To the resin from step E was added DCE (2 mL),4-(3-aminopropyl)morpholine (182 mg, 1.26 mmol), and LiClO₄ (13 mg, 0.13mmol) in ethyl ether (0.1 mL). The reaction was agitated for 22 h. Thesolution was drained and the resin washed with DCM then MeOH (3 cycles),followed by DCM (3×).

Step G:

To the resin from step F was added DCE (2 mL), butyraldehyde (45 mg,0.63 mmol), trimethyl orthoformate (0.5 mL), and Na(OAc)₃BH (134 mg,0.63 mmol) in DMF (0.3 mL). The reaction was agitated for 20 h. Thesolution was drained and the resin was washed with DCM then MeOH (3cycles), followed by DCM (3×).

Step H:

To the resin from step G was added 50% TFA/DCM (2.5 mL). The resin wasagitated for 1 h and the filtrate collected. The resin was washed with2% TFA/DCM (2×1.5 mL). The combined filtrates were concentrated to aresidue and purified by reverse-phase chromatography to furnish theproduct, quinoline-3-carboxylicacid{3-[butyl-(3-morpholin-4-yl-propyl)-amino]-2-hydroxy-propyl}amide(33.2 mg, 38.1%) as a trifluoroacetate salt. MS m/z (MI-1⁺) calcd429.2866, found 429.53;

Using the method of Example 1 and appropriately substituted reagents,the following compounds of formula (I) were synthesized:

R1 R2 R3 Calc'd Mass Found Mass 4-(phenylmethyl)phenyl H4-methoxyphenylmethyl 405.2 405.3 4-(phenylmethyl)phenyl3-methylbut-1-yl 4-methoxyphenylmethyl 475.3 475.54-(phenylmethyl)phenyl furan-2-yl 4-methoxyphenylmethyl 485.2 485.44-(phenylmethyl)phenyl 2-phenyleth-1-yl 3-(1-pyrrolidin-2-one_prop-1yl514.3 514.4 4-(phenylmethyl)phenyl 3-methylbut-1-yl3-(1-pyrrolidin-2-one_prop-1yl 480.3 480.5 4-(phenylmethyl)phenyl2-phenyleth-1-yl (2-((phenylmethoxycarbonyl)-amino)eth-1-yl) 566.3 566.54-(phenylmethyl)phenyl 3-methylbut-1-yl(2-((phenylmethoxycarbonyl)-amino)eth-1-yl) 532.3 532.5 3-methoxyphenyl2-phenyleth-1-yl 3-(1-pyrrolidin-2-one_prop-1yl 454.3 454.43-methoxyphenyl 3-methylbut-1-yl 3-(1-pyrrolidin-2-one_prop-1yl 420.3420.4 3-methoxyphenyl 2-phenyleth-1-yl(2-((phenylmethoxycarbonyl)-amino)eth-1-yl) 506.3 506.4 3-methoxyphenyl3-methylbut-1-yl (2-((phenylmethoxycarbonyl)-amino)eth-1-yl) 472.3 472.53-methylphenyl 2-phenyleth-1-yl 3-(1-pyrrolidin-2-one_prop-1yl 438.3438.4 3-methylphenyl 3-methylbut-1-yl 3-(1-pyrrolidin-2-one_prop-1yl404.3 404.4 3-methylphenyl 2-phenyleth-1-yl(2-((phenylmethoxycarbonyl)-amino)eth-1-yl) 490.3 490.4 3-methylphenyl3-methylbut-1-yl (2-((phenylmethoxycarbonyl)-amino)eth-1-yl) 456.3 456.44-(phenylmethoxy)phenyl 2-phenyleth-1-yl 3-(1-pyrrolidin-2-one_prop-1yl530.3 530.4 4-(phenylmethoxy)phenyl 3-methylbut-1-yl3-(1-pyrrolidin-2-one_prop-1yl 496.3 496.5 4-(phenylmethoxy)phenyl2-phenyleth-1-yl (2-((phenylmethoxycarbonyl)-amino)eth-1-yl) 582.3 582.54-(phenylmethoxy)phenyl 3-methylbut-1-yl(2-((phenylmethoxycarbonyl)-amino)eth-1-yl) 548.3 548.54-(phenylmethyl)phenyl 2-phenyleth-1-yl cyclohexyl 471.3 471.64-(phenylmethyl)phenyl 3-methylbut-1-yl cyclohexyl 437.3 437.54-(phenylmethyl)phenyl 2-phenyleth-1-yl cyclohexylmethyl 485.3 485.64-(phenylmethyl)phenyl 3-methylbut-1-yl cyclohexylmethyl 451.3 451.64-(phenylmethyl)phenyl 2-phenyleth-1-yl 2-phenyleth-1-yl 493.3 493.54-(phenylmethyl)phenyl 3-methylbut-1-yl 2-phenyleth-1-yl 459.3 459.64-(phenylmethyl)phenyl 3-methylbut-1-yl1-(cyclohexylaminocarbonyl)-2-(phenylmethyl) 584.4 584.74-(phenylmethyl)phenyl 2-phenyleth-1-yl 2-(4-sulfamoylphenyl)eth-1-yl572.3 572.6 4-(phenylmethyl)phenyl 3-methylbut-1-yl2-(4-sulfamoylphenyl)eth-1-yl 538.3 538.5 3-methoxyphenyl3-methylbut-1-yl 4-methylthiobutanamid-2-yl 426.2 426.4 3-methoxyphenyl2-phenyleth-1-yl cyclohexyl 411.3 411.5 3-methoxyphenyl 3-methylbut-1-ylcyclohexyl 377.3 377.5 3-methoxyphenyl 2-phenyleth-1-yl cyclohexylmethyl425.3 425.5 3-methoxyphenyl 3-methylbut-1-yl cyclohexylmethyl 391.3391.5 3-methoxyphenyl 2-phenyleth-1-yl 2-phenyleth-1-yl 433.3 433.53-methoxyphenyl 3-methylbut-1-yl 2-phenyleth-1-yl 399.3 399.53-methoxyphenyl 2-phenyleth-1-yl N-cyclohexyl-3-phenylpropanamide-2-yl558.3 558.6 3-methoxyphenyl 3-methylbut-1-ylN-cyclohexyl-3-phenylpropanamide-2-yl 524.4 524.6 3-methoxyphenyl2-phenyleth-1-yl 2-(4-sulfamoylphenyl)eth-1-yl 512.2 512.43-methoxyphenyl 3-methylbut-1-yl 2-(4-sulfamoylphenyl)eth-1-yl 478.2478.5 3-methoxyphenyl 2-phenyleth-1-yl(2-((phenylmethoxycarbonyl)-amino)eth-1-yl) 520.3 520.5 3-methoxyphenyl3-methylbut-1-yl (2-((phenylmethoxycarbonyl)-amino)eth-1-yl) 486.3 486.53-methoxyphenyl 2-phenyleth-1-yl 2-aminoeth-1-yl 372.2 372.53-methoxyphenyl 3-methylbut-1-yl 2-aminoeth-1-yl 338.2 338.44-(phenylmethyl)phenyl 3-methylbut-1-yl(2-((phenylmethoxycarbonyl)-amino)eth-1-yl) 546.3 546.64-(phenylmethyl)phenyl 2-phenyleth-1-yl 2-aminoeth-1-yl 432.3 432.44-(phenylmethyl)phenyl 3-methylbut-1-yl 2-aminoeth-1-yl 398.3 398.54-methylphenyl 3-methylbut-1-yl 2-(4-methylphenyl)eth-1-yl 397.3 397.54-methylphenyl 3-methylbut-1-yl 2-phenyleth-1-yl 383.3 383.54-methylphenyl 3-methylbut-1-yl 2-(3-fluorophenyl)eth-1-yl 401.3 401.44-methylphenyl 3-methylbut-1-yl 2-(3-methoxyphenyl)eth-1-yl 413.3 413.54-methylphenyl 3-methylbut-1-yl 2-(3,5-dimethoxyphenyl)eth-1-yl 443.3443.5 4-methylphenyl 3-methylbut-1-yl 2-(4-phenoxyphenyl)eth-1-yl 475.3475.5 4-methylphenyl 2-phenyleth-1-yl 2-(4-methylphenyl)eth-1-yl 431.3431.5 4-methylphenyl 2-phenyleth-1-yl 2-phenyleth-1-yl 417.3 417.44-methylphenyl 2-phenyleth-1-yl 2-(3-fluorophenyl)eth-1-yl 435.2 435.54-methylphenyl 2-phenyleth-1-yl 2-(3-methoxyphenyl)eth-1-yl 447.3 447.54-methylphenyl 2-phenyleth-1-yl 2-(3,5-dimethoxyphenyl)eth-1-yl 477.3477.5 4-methylphenyl 2-phenyleth-1-yl 2-(4-phenoxyphenyl)eth-1-yl 509.3509.5 phenylmethyl 3-methylbut-1-yl 2-(3-fluorophenyl)eth-1-yl 401.3401.5 phenylmethyl 3-methylbut-1-yl 2-(3-methoxyphenyl)eth-1-yl 413.3413.5 phenylmethyl 3-methylbut-1-yl 2-(3,5-dimethoxyphenyl)eth-1-yl443.3 443.5 phenylmethyl 3-methylbut-1-yl 2-(4-phenoxyphenyl)eth-1-yl475.3 475.5 phenylmethyl 2-phenyleth-1-yl 2-(3-methoxyphenyl)eth-1-yl447.3 447.5 phenylmethyl 2-phenyleth-1-yl2-(3,5-dimethoxyphenyl)eth-1-yl 477.3 477.5 phenylmethyl2-phenyleth-1-yl 2-(4-phenoxyphenyl)eth-1-yl 509.3 509.53,5-dimethoxyphenyl 3-methylbut-1-yl 2-(3,5-dimethoxyphenyl)eth-1-yl489.3 489.6 3-(dimethylamino)phenyl 3-methylbut-1-yl2-(3,4-dichlorophenyl)eth-1-yl 480.2 480.6 3-(dimethylamino)phenyl3-methylbut-1-yl 2-(3-fluorophenyl)eth-1-yl 430.3 430.63-(dimethylamino)phenyl 3-methylbut-1-yl 2-(3-methoxyphenyl)eth-1-yl442.3 442.6 3-(dimethylamino)phenyl 3-methylbut-1-yl2-(3,5-dimethoxyphenyl)eth-1-yl 472.3 472.5 3-(dimethylamino)phenyl3-methylbut-1-yl 2-(4-phenoxyphenyl)eth-1-yl 504.3 504.63-(dimethylamino)phenyl 2-phenyleth-1-yl 2-(3,4-dichlorophenyl)eth-1-yl514.2 514.5 3-(dimethylamino)phenyl 2-phenyleth-1-yl2-(3-fluorophenyl)eth-1-yl 464.3 464.6 4-acetylphenyl 3-methylbut-1-yl2-(3,4-dichlorophenyl)eth-1-yl 479.2 479.5 4-acetylphenyl3-methylbut-1-yl 2-phenyleth-1-yl 411.3 411.5 4-acetylphenyl3-methylbut-1-yl 2-(3-fluorophenyl)eth-1-yl 429.3 429.5 4-acetylphenyl3-methylbut-1-yl 2-(3-methoxyphenyl)eth-1-yl 441.3 441.6 4-acetylphenyl3-methylbut-1-yl 2-(4-phenoxyphenyl)eth-1-yl 503.3 503.6 4-acetylphenyl2-phenyleth-1-yl 2-(3,4-dichlorophenyl)eth-1-yl 513.2 513.54-acetylphenyl 2-phenyleth-1-yl 2-phenyleth-1-yl 445.3 445.64-acetylphenyl 2-phenyleth-1-yl 2-(3-methoxyphenyl)eth-1-yl 475.3 475.64-acetylphenyl 2-phenyleth-1-yl 2-(3,5-dimethoxyphenyl)eth-1-yl 505.3505.6 4-acetylphenyl 2-phenyleth-1-yl 2-(4-phenoxyphenyl)eth-1-yl 537.3537.7 3-trifluoromethylphenyl 3-methylbut-1-yl2-(3,4-dichlorophenyl)eth-1-yl 505.2 505.4 3-trifluoromethylphenyl3-methylbut-1-yl 2-phenyleth-1-yl 437.2 437.5 3-trifluoromethylphenyl3-methylbut-1-yl 2-(3-methoxyphenyl)eth-1-yl 467.3 467.63-trifluoromethylphenyl 3-methylbut-1-yl 2-(3,5-dimethoxyphenyl)eth-1-yl497.3 497.6 2-chloropyrid-4-yl 3-methylbut-1-yl2-(3,4-dichlorophenyl)eth-1-yl 472.1 472.5 2-chloropyrid-4-yl3-methylbut-1-yl 2-phenyleth-1-yl 404.2 404.5 2-chloropyrid-4-yl3-methylbut-1-yl 2-(3-fluorophenyl)eth-1-yl 422.2 422.52-chloropyrid-4-yl 3-methylbut-1-yl 2-(3-methoxyphenyl)eth-1-yl 434.2434.5 2-chloropyrid-4-yl 3-methylbut-1-yl2-(3,5-dimethoxyphenyl)eth-1-yl 464.2 464.6 2-chloropyrid-4-yl3-methylbut-1-yl 2-(4-ethylphenyl)eth-1-yl 432.2 432.52-chloropyrid-4-yl 2-phenyleth-1-yl 2-(3,4-dichlorophenyl)eth-1-yl 506.1506.4 2-chloropyrid-4-yl 2-phenyleth-1-yl 2-phenyleth-1-yl 438.2 438.52-chloropyrid-4-yl 2-phenyleth-1-yl 2-(3-fluorophenyl)eth-1-yl 456.2456.5 2-chloropyrid-4-yl 2-phenyleth-1-yl 2-(3-methoxyphenyl)eth-1-yl468.2 468.6 2-chloropyrid-4-yl 2-phenyleth-1-yl2-(3,5-dimethoxyphenyl)eth-1-yl 498.2 498.5 2-chloropyrid-4-yl2-phenyleth-1-yl 2-(4-ethylphenyl)eth-1-yl 466.2 466.6 pyrid-3-yl3-methylbut-1-yl 2-(3,4-dichlorophenyl)eth-1-yl 438.2 438.5 pyrid-3-yl3-methylbut-1-yl 2-phenyleth-1-yl 370.3 370.5 pyrid-3-yl3-methylbut-1-yl 2-(3-fluorophenyl)eth-1-yl 388.2 388.5 pyrid-3-yl3-methylbut-1-yl 2-(3,5-dimethoxyphenyl)eth-1-yl 430.3 430.5 pyrid-3-yl3-methylbut-1-yl 2-(4-ethylphenyl)eth-1-yl 398.3 398.6 pyrid-3-yl2-phenyleth-1-yl 2-(3,4-dichlorophenyl)eth-1-yl 472.2 472.5 pyrid-3-yl2-phenyleth-1-yl 2-phenyleth-1-yl 404.2 404.5 pyrid-3-yl2-phenyleth-1-yl 2-(3-fluorophenyl)eth-1-yl 422.2 422.5 pyrid-3-yl2-phenyleth-1-yl 2-(3-methoxyphenyl)eth-1-yl 434.2 434.5 pyrid-3-yl2-phenyleth-1-yl 2-(3,5-dimethoxyphenyl)eth-1-yl 464.3 464.6 pyrid-3-yl2-phenyleth-1-yl 2-(4-ethylphenyl)eth-1-yl 432.3 432.5 pyrazin-2-yl3-methylbut-1-yl 2-(3,4-dichlorophenyl)eth-1-yl 439.2 439.4 pyrazin-2-yl3-methylbut-1-yl 2-phenyleth-1-yl 371.2 371.5 pyrazin-2-yl3-methylbut-1-yl 2-(3-fluorophenyl)eth-1-yl 389.2 389.5 pyrazin-2-yl3-methylbut-1-yl 2-(3-methoxyphenyl)eth-1-yl 401.3 401.5 pyrazin-2-yl3-methylbut-1-yl 2-(3,5-dimethoxyphenyl)eth-1-yl 431.3 431.5pyrazin-2-yl 3-methylbut-1-yl 2-(4-ethylphenyl)eth-1-yl 399.3 399.5pyrazin-2-yl 2-phenyleth-1-yl 2-(3,4-dichlorophenyl)eth-1-yl 473.2 473.5pyrazin-2-yl 2-phenyleth-1-yl 2-phenyleth-1-yl 405.2 405.5 3-quinolylbutyl 2-(morpholin-4-yl)prop-3-yl 429.3 429.5 3-quinolyl butyl2-(2-pyridyl)eth-1yl 407.2 407.5 3-quinolyl butyl 2-(2-thienyl)eth-1yl412.2 412.4 3-quinolyl butyl 2-(1-pyrrolidin-2-one_eth-1yl 427.3 427.53-quinolyl butyl 2-(2-methyl-1-piperidinyl)eth-1-yl 441.3 441.63-quinolyl butyl 2-(4-ethylphenyl)eth-1-yl 434.3 434.5 3-quinolyl3-methylbut-1-yl 2-(morpholin-4-yl)prop-3-yl 443.3 443.6 3-quinolyl3-methylbut-1-yl 2-(2-pyridyl)eth-1yl 421.3 421.5 3-quinolyl3-methylbut-1-yl 2-(2-thienyl)eth-1yl 426.2 426.5 3-quinolyl3-methylbut-1-yl 2-(2-methyl-1-piperidinyl)eth-1-yl 455.3 455.73-quinolyl 3-methylbut-1-yl 2-(4-ethylphenyl)eth-1-yl 448.3 448.6cyclohexyl butyl 2-(2-pyridyl)eth-1yl 362.3 362.5 cyclohexyl butyl2-(2-thienyl)eth-1yl 367.2 367.5 cyclohexyl butyl2-(2-methyl-1-piperidinyl)eth-1-yl 396.4 396.4 cyclohexyl butyl2-(4-ethylphenyl)eth-1-yl 389.3 389.6 cyclohexyl 3-methylbut-1-yl2-(2-pyridyl)eth-1yl 376.3 376.6 cyclohexyl 3-methylbut-1-yl2-(2-thienyl)eth-1yl 381.3 381.5 cyclohexyl 3-methylbut-1-yl2-(1-pyrrolidin-2-one_eth-1 yl 396.3 396.3 cyclohexyl 3-methylbut-1-yl2-(2-methyl-1-piperidinyl)eth-1-yl 410.4 410.4 cyclohexyl3-methylbut-1-yl 2-(4-ethylphenyl)eth-1-yl 403.3 403.6 methylthiomethylbutyl 2-(morpholin-4-yl)prop-3-yl 362.3 362.2 methylthiomethyl butyl2-(2-pyridyl)eth-1yl 340.2 340.2 methylthiomethyl butyl2-(2-thienyl)eth-1yl 345.2 345.4 methylthiomethyl butyl2-(1-pyrrolidin-2-one_eth-1yl 360.2 360.5 methylthiomethyl butyl2-(2-methyl-1-piperidinyl)eth-1-yl 374.3 374.5 methylthiomethyl butyl2-(4-ethylphenyl)eth-1-yl 367.2 367.5 methylthiomethyl 3-methylbut-1-yl2-(morpholin-4-yl)prop-3-yl 376.3 376.5 methylthiomethyl3-methylbut-1-yl 2-(2-pyridyl)eth-1yl 354.2 354.5 methylthiomethyl3-methylbut-1-yl 2-(2-thienyl)eth-1yl 359.2 359.4 methylthiomethyl3-methylbut-1-yl 2-(2-methyl-1-piperidinyl)eth-1-yl 388.3 388.5methylthiomethyl 3-methylbut-1-yl 2-(4-ethylphenyl)eth-1-yl 381.3 381.53-methylfur-2-yl butyl 2-(morpholin-4-yl)prop-3-yl 382.3 382.63-methylfur-2-yl butyl 2-(2-pyridyl)eth-1yl 360.2 360.5 3-methylfur-2-ylbutyl 2-(2-thienyl)eth-1yl 365.2 365.5 3-methylfur-2-yl butyl2-(1-pyrrolidin-2-one_eth-1 yl 380.3 380.5 3-methylfur-2-yl butyl2-(2-methyl-1-piperidinyl)eth-1-yl 394.3 394.6 3-methylfur-2-yl butyl2-(4-ethylphenyl)eth-1-yl 387.3 387.5 3-methylfur-2-yl 3-methylbut-1-yl2-(morpholin-4-yl)prop-3-yl 396.3 396.6 3-methylfur-2-yl3-methylbut-1-yl 2-(2-pyridyl)eth-1yl 374.2 374.5 3-methylfur-2-yl3-methylbut-1-yl 2-(2-thienyl)eth-1yl 379.2 379.5 3-methylfur-2-yl3-methylbut-1-yl 2-(2-methyl-1-piperidinyl)eth-1-yl 408.3 408.63-methylfur-2-yl 3-methylbut-1-yl 2-(4-ethylphenyl)eth-1-yl 401.3 401.5phenylmethoxy 3-methylbut-1-yl 3-benzoxyphenyl 534.3 534.6 phenylmethoxy3-methylbut-1-yl naphth-1-ylmethyl 492.3 492.6 phenylmethoxy2-phenyleth-1-yl naphth-1-ylmethyl 526.3 526.5 phenylmethoxy3-methylbut-1-yl 1-benzylpiperidin-4-yl 525.3 525.6 phenylmethoxy3-methylbut-1-yl 2-(N-(3-methylphenyl)-N-ethylamino)eth-1-yl 513.3 513.6phenylmethoxy 2-phenyleth-1-yl2-(N-(3-methylphenyl)-N-ethylamino)eth-1-yl 547.3 547.6 phenylmethoxy3-methylbut-1-yl 2-phenoxyeth-1-yl 472.3 472.6 phenylmethoxy2-phenyleth-1-yl 2-phenoxyeth-1-yl 506.3 506.5 acetamidomethyl2-phenyleth-1-yl naphth-1-ylmethyl 434.2 434.5 acetamidomethyl3-methylbut-1-yl 2-(N-(3-methylphenyl)-N-ethylamino)eth-1-yl 421.3 421.5acetamidomethyl 2-phenyleth-1-yl2-(N-(3-methylphenyl)-N-ethylamino)eth-1-yl 455.3 455.6 phenylmethoxy3-methylbut-1-yl 4-phenoxyphenyl 534.3 534.6 phenylmethoxy2-phenyleth-1-yl 4-phenoxyphenyl 568.3 568.6 phenylmethoxy3-methylbut-1-yl 3-benzoxyphenyl 548.3 548.6 phenylmethoxy2-phenyleth-1-yl 3-benzoxyphenyl 582.3 582.6 phenylmethoxy3-methylbut-1-yl naphth-1-ylmethyl 506.3 506.5 phenylmethoxy2-phenyleth-1-yl naphth-1-ylmethyl 540.3 540.6 phenylmethoxy3-methylbut-1-yl 1-benzylpiperidin-4-yl 539.4 539.6 phenylmethoxy2-phenyleth-1-yl 1-benzylpiperidin-4-yl 573.3 573.7 phenylmethoxy3-methylbut-1-yl 2-(N-(3-methylphenyl)-N-ethylamino)eth-1-yl 527.4 527.6phenylmethoxy 2-phenyleth-1-yl2-(N-(3-methylphenyl)-N-ethylamino)eth-1-yl 561.3 561.7 phenylmethoxy3-methylbut-1-yl 2-phenoxyeth-1-yl 486.3 486.6 phenylmethoxy2-phenyleth-1-yl 2-phenoxyeth-1-yl 520.3 520.5 pyran-2-one-4-yl H2-(1-pyrrolidin-2-one_eth-1yl 338.2 338.5 pyran-2-one-4-yl Hcyclopropylmethyl 267.1 267.5 pyran-2-one-4-yl H2-(2-methyl-1-piperidinyl)eth-1-yl 352.2 352.6 pyran-2-one-4-yl Hcyclohexylmethyl 309.2 pyran-2-one-4-yl H tetrahydrofuran-2-yl 297.2297.5 2-cyclopentyleth-1-yl H 2-(morpholin-4-yl)prop-3-yl 342.3 342.62-cyclopentyleth-1-yl H 2-(2-methyl-1-piperidinyl)eth-1-yl 354.3 354.72-cyclopentyleth-1-yl H cyclohexylmethyl 311.3 311.62-cyclopentyleth-1-yl 4-methoxyphenylmethyl tetrahydrofuran-2-yl 419.3419.7 2-cyclopentyleth-1-yl 4-methoxyphenylmethyl cyclopropylmethyl389.3 389.7 2-cyclopentyleth-1-yl H tetrahydrofuran-2-yl 299.2 299.62-cyclopentyleth-1-yl H cyclopropylmethyl 269.2 269.5methysulfonylmethyl H 3-(2-methyl-1-piperidinyl)prop-1-yl 350.2 349.6methysulfonylmethyl H cyclohexylmethyl 307.2 307.5 2-phenylethyn-1-yl H2-(morpholin-4-yl)prop-3-yl 346.2 346.6 2-phenylethyn-1-yl H3-(2-methyl-1-piperidinyl)prop-1-yl 358.3 358.6 2-phenylethyn-1-yl Hcyclohexylmethyl 315.2 315.5 2-phenylethyn-1-yl H tetrahydrofuran-2-yl303.2 303.5 2-cyclopentyleth-1-yl 4-isopropylphenylmethyl3-(1-pyrrolidin-2-one_prop-1yl 472.4 472.8 2-cyclopentyleth-1-yl4-isopropylphenylmethyl 3-(2-methyl-1-piperidinyl)prop-1-yl 486.4 486.92-cyclopentyleth-1-yl 4-isopropylphenylmethyl cyclohexylmethyl 443.4443.8 2-cyclopentyleth-1-yl 4-isopropylphenylmethyl tetrahydrofuran-2-yl431.3 431.7 2-cyclopentyleth-1-yl 4-isopropylphenylmethylcyclopropylmethyl 401.3 401.7 2-phenylethyn-1-yl 4-methoxyphenylmethylcyclohexylmethyl 435.3 435.7 2-phenylethyn-1-yl 4-methoxyphenylmethyltetrahydrofuran-2-yl 423.2 423.6 2-phenylethyn-1-yl4-isopropylphenylmethyl 3-(1-pyrrolidin-2-one_prop-1yl 476.3 476.8

Example 2

Step A:

To the Alloc-Rink AM resin (200 mg, 0.13 mmol) was added DCE (2 mL) andPhSiH₃ (130 uL, 1.04 mmol). The solution was bubbled with nitrogen andthen Pd(PPh₃)₄ (30 mg, 0.02 mmol) was added. The reaction mixture wasbubbled with nitrogen for 2 h. The solution was drained and the resinwashed with DCM then MeOH (3 cycles), followed by DCM (3×).

Step B:

To the resin from step A was added DCE (2 mL), diisopropylethylamine(0.25 mL), diphenylmethane-4-carboxylic acid (106 mg, 0.50 mmol), and2-chloro-1,3-dimethylimidazolidinium chloride (106 mg, 0.63 mmol). Thereaction mixture was agitated for 18 h. The solution was drained and theresin washed with DCM then MeOH (3 cycles), followed by DCM (3×).

Step C:

To the resin from step B was added DCE (2 mL), piperidine (107 mg, 1.26mmol), and LiClO₄ (13 mg, 0.13 mmol). The reaction was agitated for 20h. The solution was drained and the resin washed with DCM then MeOH (3cycles), followed by DCM (3×).

Step D:

To the resin from step C was added 50% TFA/DCM (2.5 mL). The resin wasagitated for 1 h and the filtrate collected. The resin was washed with2% TFA/DCM (2×1.5 mL). The combined filtrates were concentrated to aresidue and purified by reverse-phase chromatography to furnish theproduct, 4-Benzyl-N-(2-hydroxy-3-piperidin-1-yl-propyl)-benzamide (13mg, 0.028 mmol) as a trifluoroacetate salt. MS m/z (MH⁺) calcd 353.2,found 353.4.

1. A method of synthesizing a hydroxyethylamino amide of Formula (I):

wherein: R¹ is C₅₋₁₄heteroaryl C₂₋₈alkenyl, heteroaryl(C₂₋₈)alkenyl, orheteroaryl(C₂₋₈)alkynyl; C₅₋₁₄heteroaryl C₂₋₈alkenyl,heteroaryl(C₂₋₈)alkenyl, and heteroaryl(C₂₋₈)alkynyl are optionallysubstituted with one to two substituents independently selected from thegroup consisting of C₆₋₁₄aryloxy, diC₁₋₈ alkanylamino, C₁₋₈alkanylamino, C₁₋₈alkanyl, C₆₋₁₄aryl, C₁₋₈alkanyloxy,C₁₋₈alkanylcarbonyl, perhaloC₁₋₆alkanyl, halo, C₅₋₁₄heteroaryl, C₁₋₈alkanyl, C₁₋₈alkanylthio, oxoC₅ ₋₈ cyclicheteroalkenyl,C₆₋₁₄arylalkynyl, C₁₋₈alkanylsulfonyl, C₆₋₁₄arylC₁₋₈alkanyl,C₁₋₈alkanyloxy, C₆₋₁₄arylC₁₋₈alkanyloxy,C₆₋₁₄arylC₁₋₈alkanyloxycarbonylamino, and C₁₋₈alkanylcarbonylamino; R²is C₁₋₈alkanyl, C₂₋₈alkenyl, C₁₋₈alkoxy(C₂₋₈)alkenyl, C₂₋₈alkynyl,C₁₋₈alkanyloxy(C₂₋₈)alkynyl, heteroaryl(C₂₋₈)alkenyl,heteroaryl(C₂₋₈)alkynyl, hydrogen, or-N-linked-C₁₋₈alkanylcarbonylamino,wherein the C₁₋₈alkanyl, C₁₋₈alkenyl C₂₋₈alkynyl portions of R² areoptionally substituted with one or two substituents independentlyselected from the group consisting of C₁₋₈alkanylC₆₋₁₄aryl,C₁₋₈alkanyloxyC₆₋₁₄aryl, C₅₋₁₄heteroaryl, C₆₋₁₄aryl, or C₆₋₁₄aryl; R³ isalkanyl, C₂₋₈alkenyl, C₁₋₈alkoxy(C₂₋₈)alkenyl, C₂₋₈alkynyl,C₁₋₈alkoxy(C₂₋₈)alkynyl, heteroaryl(C₂₋₈)alkenyl,heteroaryl(C₂₋₈)alkynyl, C₁₋₈alkanyl, cyclicC₁₋₈alkanyl, C₆₋₁₄aryl, orC₅₋₁₄heteroaryl; wherein said C₁₋₈alkanyl, cyclicC₁₋₈alkanyl, C₆₋₁₄aryl,and C₅₋₁₄heteroaryl is optionally and independently substituted with oneor two substituent selected from the group consisting of(C₁₋₈alkanylthio)(aminocarbonyl), C₁₋₈alkanylaminocarbonyl,(C₆₋₁₄aryl)(C₁₋₈alkanylaminocarbonyl), amino, aminosulfonylC₆₋₁₄aryl,C₁₋₈alkanylC₃₋₈cyclicheteroalkanyl, C₁₋₈alkanyloxycarbonylamino,C₁₋₈alkanylC₆₋₁₄arylamino, C₁₋₈alkanylC₆₋₁₄aryl,C₁₋₈alkanyloxyC₆₋₁₄aryl, C₃₋₈cyclicheteroalkanyl, C₆₋₁₄aryl, C₆₋₁₄arylC₁₋₈alkanyloxycarbonylamino, C₆₋₁₄aryloxy, C₆₋₁₄aryloxyC₆₋₁₄aryl,diC₁₋₈alkanyloxyC₆₋₁₄aryl, dihaloC₆₋₁₄aryl haloC₆₋₁₄aryl, andoxoC₃₋₈cyclicheteroalkanyl; C₆₋₁₄aryl wherein said aryl is optionallyand independently substituted with a substituent selected from the groupconsisting of C₁₋₈alkanyl, and C₆₋₁₄aryloxy;C₁₋₈alkanylC₃₋₈cyclicheteroalkanyl; C₅₋₁₄heteroaryl;C₆₋₁₄arylC₁₋₈alkanylheteroalkanyl; or C₃₋₈cyclicheteroalkanyl; and anenantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptablesalt thereof, the method comprising: (a) preparing a epoxymethylatedsupport of formula (Ia)

wherein (support) is selected from the group consisting of amine basedpolystyrene resins; (b) reacting the support of formula (Ia) with an R¹carboxylic acid or derivative of the formula R¹COY wherein Y is OH, Cl,Br, OC₁₋₃alkanyl or OOCR¹ to generate an epoxymethylated amido supportof formula (Ib)

(c) reacting the epoxymethylated amido support of formula (Ib) with anR² amine of the formula R²NH₂ to generate a hydroxyethylamino amidosupport of formula (Ic)

(d) reacting the hydroxyethylamino amido support of formula (Ic) with anR³ aldehyde of the formula R³CHO to generate a hydroxyethylamino amidosupport of formula (Id)

and (e) cleaving the hydroxyethlamino amide of formula (I) from thehydroxyethlamino amido support of formula (Id).
 2. The method accordingto claim 1 wherein Y is OH.
 3. The method according to claim 1 wherein(support) is a Rink resin.
 4. The method according to claim 1 wherein(support) is Rink-AM resin.
 5. The method according to claim 1 whereinR¹ is optionally substituted pyridyl and pyrazinyl, quinolyl, or furyl;R² is hydrogen, C₁₋₈alkanyloxyC₆₋₁₄arylC₁₋₈alkanyl, orC₁₋₈alkanylC₆₋₁₄arylC₁₋₈alkanyl; and R³ is optionally substitutedC₁₋₈alkanyl. 6.-7. (canceled)
 8. A method of synthesizing ahydroxyethylamino amide of Formula (I):

wherein: R¹ is C₅₋₁₄heteroaryl; wherein said C₅₋₁₄heteroaryl isoptionally substituted with one to two substituents independentlyselected from the group consisting of C₆₋₁₄ aryloxy, diC₁₋₈alkanylamino,C₁₋₈alkanylamino, C₁₋₈alkanyl, C₆₋₁₄aryl, C₁₋₈alkanyloxy,C₁₋₈alkanylcarbonyl, perhaloC₁₋₆alkanyl, halo, C₅₋₁₄heteroaryl,C₁₋₈alkanyl, C₁₋₈alkanylthio, oxoC₅₋₈cyclicheteroalkenyl,C₆₋₁₄arylalkynyl, C₁₋₈alkanylsulfonyl, C₆₋₁₄arylC₁₋₈alkanyl,C₁₋₈alkanyloxy, C₆₋₁₄arylC₁₋₈alkanyloxy,C₆₋₁₄arylC₁₋₈alkanyloxycarbonylamino, and C₁₋₈alkanylcarbonylamino; R²is C₁₋₈alkanyl, C₁₋₈alkenyl, hydrogen, orN-linked-C₁₋₈alkanylcarbonylamino, wherein said C₁₋₈alkanyl andC₁₋₈alkenyl are optionally substituted with one or two substituentsindependently selected from the group consisting ofC₁₋₈alkanylC₆₋₁₄aryl, C₁₋₈alkanyloxyC₆₋₁₄aryl, C₅₋₁₄heteroaryl,C₆₋₁₄aryl, or C₆₋₁₄aryl; R³ is C₁₋₈alkanyl wherein said C₁₋₈alkanyl isoptionally and independently substituted with one or two substituentselected from the group consisting of (C₁₋₈alkanylthio)(aminocarbonyl),C₁₋₈alkanylaminocarbonyl, (C₆₋₁₄aryl)(C₁₋₈alkanylaminocarbonyl), amino,aminosulfonylC₆₋₁₄aryl, C₁₋₈alkanylC₃₋₈cyclicheteroalkanyl,C₁₋₈alkanyloxycarbonylamino, C₁₋₈alkanylC₆₋₁₄arylamino,C₁₋₈alkanylC₆₋₁₄aryl, C₁₋₈alkanyloxyC₆₋₁₄aryl, C₃₋₈cyclicheteroalkanyl,C₆₋₁₄aryl, C₆₋₁₄arylC₁₋₈alkanyloxycarbonylamino, C₆₋₁₄aryloxy,C₆₋₁₄aryloxyC₆₋₁₄aryl, diC₁₋₈alkanyloxyC₆₋₁₄aryl, dihaloC₆₋₁₄arylhaloC₆₋₁₄aryl, and oxoC₃₋₈cyclicheteroalkanyl; C₆₋₁₄aryl wherein saidaryl is optionally and independently substituted with a substituentselected from the group consisting of C₁₋₈alkanyl, and C₆₋₁₄aryloxy;C₁₋₈alkanylC₃₋₈cyclicheteroalkanyl; C₅₋₁₄heteroaryl;C₆₋₁₄arylC₁₋₈alkanylheteroalkanyl; or C₃₋₈cyclicheteroalkanyl; and andan enantiomer, a diastereomer, a tautomer, or a pharmaceuticallyacceptable salts thereof, the method comprising: (a) preparing aepoxymethylated support of formula (Ia)

wherein (support) is selected from the group consisting of amine basedpolystyrene resins; (b) reacting the support of formula (Ia) with an R¹carboxylic acid or derivative of the formula R¹COY wherein Y is OH, Cl,Br, OC₁₋₃alkanyl or OOCR¹ to generate an epoxymethylated amido supportof formula (Ib)

(c) reacting the epoxymethylated amido support of formula (Ib) with anR² amine of the formula R²NH₂ to generate a hydroxyethylamino amidosupport of formula (Ic)

(d) reacting the hydroxyethlamino amido support of formula (Ic) with anR³ aldehyde of the formula R³CHO to generate a hydroxyethlaminohydroxyethylamino amido support of formula (Id)

and (e) cleaving the hydroxyethylamino amide of formula (I) from thehydroxyethlamino amido support of formula (Id).
 9. The method accordingto claim 8 wherein Y is OH.
 10. The method according to claim 8 wherein(support) is a Rink resin.
 11. The method according to claim 8 wherein(support) is Rink-AM resin.
 12. The method according to claim 8 whereinR¹ is optionally substituted pyridyl and pyrazinyl, quinolyl, or furyl;R² is hydrogen, C₁₋₈alkanyloxyC₆₋₁₄arylC₁₋₈alkanyl, orC₁₋₈alkanylC₆₋₁₄arylC₁₋₈alkanyl; and R³ is optionally substitutedC₁₋₈alkanyl. 13.-14. (canceled)
 15. A method of synthesizing ahydroxyethylamino amide of Formula (I):

wherein: R¹ is heteroaryl(C₂₋₈)alkenyl, or heteroaryl(C₂₋₈)alkynyl;wherein said heteroaryl(C₂₋₈)alkenyl, and heteroaryl(C₂₋₈)alkynyl areoptionally substituted with one to two substituents independentlyselected from the group consisting of C₆₋₁₄aryloxy, diC₁₋₈alkanylamino,C₁₋₈alkanylamino, C₁₋₈alkanyl, C₆₋₁₄aryl, C₁₋₈alkanyloxy,C₁₋₈alkanylcarbonyl, perhaloC₁₋₆alkanyl, halo, C₅₋₁₄heteroaryl,C₁₋₈alkanyl, C₁₋₈alkanylthio, oxoC₅₋₈cyclicheteroalkenyl,C₆₋₁₄arylalkynyl, C₁₋₈alkanylsulfonyl, C₆₋₁₄arylC₁₋₈alkanyl,C₁₋₈alkanyloxy, C₆₋₁₄arylC₁₋₈alkanyloxy,C₆₋₁₄arylC₁₋₈alkanyloxycarbonylamino, and C₁₋₈alkanylcarbonylamino; R²is C₁₋₈alkanyl, C₂₋₈alkenyl, C₁₋₈alkoxy(C₂₋₈)alkenyl, C₂₋₈alkynyl,C₁₋₈alkanyloxy(C₂₋₈)alkynyl, heteroaryl(C₂₋₈)alkenyl,heteroaryl(C₂₋₈)alkynyl, or hydrogen, wherein the C₁₋₈alkanyl,C₁₋₈alkenyl C₂₋₈alkynyl portions of R² are optionally substituted withone or two substituents independently selected from the group consistingof C₁₋₈alkanylC₆₋₁₄aryl, C₁₋₈alkanyloxyC₆₋₁₄aryl, C₅₋₁₄heteroaryl,C₆₋₁₄aryl, or C₆₋₁₄aryl; or taken together with the nitrogen atom towhich they are attached, R² and R³ form a 4-7 memberedcyclicheteroalkanyl wherein the cyclicheteroalkanyl optionally containsin addition to the nitrogen atom one or 2 additional heteroatomsselected from the group consisting of N, O and S, and wherein thecyclicheteroalkanyl is optionally substituted with C₁₋₈alkanyl,C₂₋₈alkenyl, C₁₋₈alkoxy(C₂₋₈)alkenyl, C₂₋₈alkynyl,C₁₋₈alkanyloxy(C₂₋₈)alkynyl, heteroaryl(C₂₋₈)alkenyl,heteroaryl(C₂₋₈)alkynyl, or hydrogen, wherein the C₁₋₈alkanyl,C₁₋₈alkenyl C₂₋₈alkynyl portions of cyclicheteroalkanyl substitution areoptionally substituted with one or two substituents independentlyselected from the group consisting of C₁₋₈alkanylC₆₋₁₄aryl,C₁₋₈alkanyloxyC₆₋₁₄aryl, C₅₋₁₄heteroaryl, C₆₋₁₄aryl, or C₆₋₁₄aryl; R³ isC₁₋₈alkanyl, C₂₋₈alkenyl, C₁₋₈alkoxy(C₂₋₈)alkenyl, C₂₋₈alkynyl,C₁₋₈alkoxy(C₂₋₈)alkynyl, heteroaryl(C₂₋₈)alkenyl,heteroaryl(C₂₋₈)alkynyl, C₁₋₈alkanyl, cyclicC₁₋₈alkanyl, C₆₋₁₄aryl, orC₅₋₁₄heteroaryl; wherein said C₁₋₈alkanyl, cyclicC₁₋₈alkanyl, C₆₋₁₄aryl,and C₅₋₁₄heteroaryl is optionally and independently substituted with oneor two substituent selected from the group consisting of(C₁₋₈alkanylthio)(aminocarbonyl), C₁₋₈alkanylaminocarbonyl,(C₆₋₁₄aryl)(C₁₋₈alkanylaminocarbonyl), amino, aminosulfonylC₆₋₁₄aryl,C₁₋₈alkanylC₃₋₈cyclicheteroalkanyl, C₁₋₈alkanyloxycarbonylamino,C₁₋₈alkanylC₆₋₁₄arylamino, C₁₋₈alkanylC₆₋₁₄aryl,C₁₋₈alkanyloxyC₆₋₁₄aryl, C₃₋₈cyclicheteroalkanyl, C₆₋₁₄aryl,C₆₋₁₄arylC₁₋₈alkanyloxycarbonylamino, C₆₋₁₄aryloxy,C₆₋₁₄aryloxyC₆₋₁₄aryl, diC₁₋₈alkanyloxyC₆₋₁₄aryl, dihaloC₆₋₁₄arylhaloC₆₋₁₄aryl, and oxoC₃₋₈cyclicheteroalkanyl; C₆₋₁₄aryl wherein saidaryl is optionally and independently substituted with a substituentselected from the group consisting of C₁₋₈alkanyl, and C₆₋₁₄aryloxy;C₁₋₈alkanylC₃₋₈cyclicheteroalkanyl; C₅₋₁₄heteroaryl;C₆₋₁₄arylC₁₋₈alkanylheteroalkanyl; or C₃₋₈cyclicheteroalkanyl; and anenantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptablesalt thereof, the method comprising: (a) preparing a epoxymethylatedsupport of formula (Ia)

wherein (support) is a Rink-AM resin; (b) reacting the support offormula (Ia) with an R¹ carboxylic acid or derivative of the formulaR¹COY wherein Y is OH, Cl, Br, OC₁₋₃alkanyl or OOCR¹ to generate anepoxymethylated amido support of formula (Ib)

(c) reacting the epoxymethylated amido support of formula (Ib) with ansecondary amine of the formula R²R³NH to generate a hydroxyethylaminoamido support of formula (Ic)

and (e) cleaving the hydroxyethylamino amide of formula (I) from thehydroxyethylamino amido support of formula (Id).
 16. The methodaccording to claim 15 wherein taken together with the nitrogen atom towhich they are attached, R² and R³ form a 4-7 memberedcyclicheteroalkanyl wherein the cyclicheteroalkanyl optionally containsin addition to the nitrogen atom one or 2 additional heteroatomsselected from the group consisting of N, O and S, and wherein thecyclicheteroalkanyl is optionally substituted with C₁₋₈alkanyl,C₂₋₈alkenyl, C₁₋₈alkoxy(C₂₋₈)alkenyl, C₂₋₈ alkynyl,C₁₋₈alkanyloxy(C₂₋₈)alkynyl, heteroaryl(C₂₋₈)alkenyl,heteroaryl(C₂₋₈)alkynyl, or hydrogen, wherein the C₁₋₈alkanyl,C₁₋₈alkenyl C₂₋₈alkynyl portions of cyclicheteroalkanyl substitution areoptionally substituted with one or two substituents independentlyselected from the group consisting of C₁₋₈alkanylC₆₋₁₄aryl,C₁₋₈alkanyloxyC₆₋₁₄aryl, C₅₋₁₄heteroaryl, C₆₋₁₄aryl, or C₆₋₁₄aryl; 17.The method according to claim 15 wherein R²R³NH is azetidine,pyrrolidine, piperidine, N-C₁₋₃alkylpiperazine, 3-pyrroline, ormorpholine. 18.-23. (canceled)